Heterogeneous pathogenicity of retroviruses: lessons from birds, primates, and rodents

Heterogeneous Pathogenicity of Retroviruses: Lessons from Birds, Primates, and Rodents Jan Svoboda, Josef Geryk, and Daniel Elleder Institute of Molecular Genetics~ Academy of Sciences of the Czech Republic, 166 37 Prague, Czech Republic

I. Introduction II. Overview of Retroviruses III. Changes in Retrovirus Oncogenic and Pathogenic Potential by Selection, Mutation, and Recombination A. Increasing Retrovirus Replication B. Acquisition and Activation of Oncogenes C. Viral Genome Alteration and Pathogenicity IV. Retroviruses from within V. Ontogeny-Dependent Retrovirus Pathogenicity VI. Subversion of Immunity VII. Heterotransmission of Retroviruses VIII. Summary and Outlook References

" . . . the great variety of tumours and still other facts described emphasize the instability and the great capacity for variation of the viruses inducing the tumours " (DuranReynals, 1942).

I. INTRODUCTION Retroviruses, also known under other cryptonyms, originally with dismay as tumor agents, later as RNA tumor viruses and oncornaviruses, were isolated at the beginning of the last century. For a long time they were kept at the periphery of scientific interest. However, the advent of advanced tissue culture technology employed in the 1960s, followed by application of methods in molecular biology, created a great interest in retrovirus research, which laid the foundation for understanding the unusual features of retrovirus replication and the genetic basis of their cell transformation ability. This retrovirus research, performed mainly with avian retroviruses, was Advances in CANCER RESEARCH 0065-230X]03 $35.00

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Copyright 2003, Elsevier Science (USA). All rights reserved.

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awarded three Nobel prizes in relatively short intervals. It is therefore not surprising that the retrovirus field has been reviewed repeatedly. The most thorough summary was published by Teich et aI. (1984). There appeared a very good series of articles covering different aspects of retrovirology, having the common denomination Retroviridae (ed. J. A. Levy, 1992). Very pertinent to our article is its chapter 6 written by L. N. Payne. An attractive overview of further progress in the retrovirus field has been published by Coffin et al. (1997). In this series, avian retroviruses have been discussed critically several times, most recently by Enrietto and Wyke (1983). In order to avoid extensive overlapping with already published reviews, we decided to look at the retrovirus field from the point of view of both viral and host factors (defined or undefined thus far) involved in various manifestations of retrovirus pathogenicity as reported in recent publications. Because of imposed limits, we can open only selected windows, and we therefore discuss in more depth a few examples of retrovirus-induced diseases that have been well documented and/or illustrate the complexity of disease manifestations. The first part of this review covers the essential structural features and genetic properties of retroviruses, which provide a framework for further sections. In this connection, we discuss selected virus-acquired oncogenes and their function. The oncogene research triggered by the discovery of viral oncogenes became of prime importance to oncology, and therefore specialized monographs have been devoted to them. Because of the extensive coverage of the topic of oncogenes, we give only a general overview and discuss the function of only two oncogenes. There are well-recognized host-dependent conditions that alter retroviral pathogenicity. They include the ontogenic maturity of the host, which usually also influences the extent of virus persistence and immunopathogenicity. Furthermore, as revealed in several cases, but mostly elaborated with the simian immunodeficiency virus (SIV), the course of retrovirus infection can be strongly modified in the heterologous host and new unwelcome consequences may emerge.

II. OVERVIEW OF RETROVIRUSES The retrovirus family was given a self-explanatory name because the key position of the virus replication cycle is held by the virus-coded multifunctional enzyme reverse transcriptase (RT). In a series of remarkably orchestrated steps, RT catalyzes the conversion of viral genomic RNA into a linear double-stranded DNA copy. The DNA is subsequently integrated into the cell genome as a provirus in reactions catalyzed by the viral integrase enzyme. Classical relatively simple avian or mammalian retroviruses previously called type C (now ~ and y retroviruses, respectively) have three

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genes required for virus replication contained in the viral RNA genome: gag coding for the viral structural proteins, pol for RT and integrase, and env for a glycoprotein constituting the envelope of the viral particle composed of a surface knob-like domain (SU) and a transmembrane domain (TM). Reverse transcription does not change the order of viral replicative genes but generates long terminal repeats (LTR), which flank proviral DNA and provide strong promotor-enhancer signals. Figure 1A shows a schematic diagram of the Prague strain of the Rous sarcoma virus (PR-RSV) genome. Like other RSV strains, PR-RSV acquired an additional gene, oncogene v-src, at its 3' end. Any retrovirus that keeps replicative genes intact is replication competent. Conversely, once any replication gene is damaged, a virus becomes defective and can replicate only when complemented by another retrovirus (usually called a helper virus), which provides the missing gene product. Predominant retroviruses that originated in avian species, called avian leukosis viruses (ALV), are replication competent and usually produce leukemias after several months of incubation. Because of an almost total identity

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in viral replicative genes, for practical reasons they are grouped together with the oncogene v-src-containing acute sarcomagenic viruses such as avian leukosis sarcoma viruses (ALSV). Another group of interesting avian retroviruses, which, according to several characteristic features, resulted from a horizontal transfer from mammals to avian species, is represented by reticuloendotheliosis viruses (REV) and is dealt with later in Section VI. Among mammalian type C retroviruses, the most thoroughly studied viruses are Friend murine leukemia virus (Fr-MLV), a defective virus causing erythroleukemia, and Moloney murine leukemia virus (Mo-MLV) inducing T-cell lymphoid tumors. The extremely defective virus BM5 triggers the mouse acquired immunodeficiency syndrome (MAIDS). Another group of retroviruses, classified as genus Lentivirus, acquired six accessory genes (Fig. 1B), which impart beneficial effects on different stages of the virus life cycle. Of special importance is the nef regulatory gene, also acting as a link between the virus life cycle and lymphoid cell deregulation; mutation of nef can seriously impair virus replication in vivo (see Section VII). Among the best-known lentiviruses are human immunodeficiency viruses HIV-1 and HIV-2 and a series of SIV strains, which are discussed later. The bovine leukemia virus (BLV) has an intermediate position between C type and lentiviruses, as it is endowed with only two accessory genes. Despite the differences in the structure and complexity of viral genome regulation, retroviruses follow a common pattern in their life cycle and replication. As shown schematically in Fig. 2, retrovirus Env glycoproteins interact with cognate receptors (in lentiviruses, coreceptors have also been recognized) on the cell membrane, which turns on fusion between the viral particle and the cell membrane, allowing virus entry into the cytoplasm. Retroviruses are usually arranged in categories called subgroups. Viruses belonging to the same subgroup employ for their entry into a cell a common cellular receptor. Reverse transcription of viral genomic RNA to DNA is mediated by RT, the product of the viral gene pol, and takes place in the cytoplasm. Newly synthesized viral DNA is transported to the nucleus, where it integrates into cellular genomic DNA as a provirus. Once the provirus becomes an integral part of the cell genome, it is subjected to complete control by the cell, which includes DNA repair and provirus expression. Synthesis of the virus progeny starts with provirus transcription, yielding full-length genomic RNA, which also codes for Gag and Pol viral proteins. Other proteins, such as the Env glycoproteins, are encoded by spliced subgenomic RNA species. New virions assemble on the cell membrane and are released by the budding process. An important characteristic of retroviruses, underscored in Fig. 2, lies in the fact that every virion contains two viral genomic RNAs, which means that retroviral genomes are essentially diploid. If a cell is infected with two

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virions differing in their genetic makeup, then half of the virus progeny will consist of heterozygous particles containing mixed RNAs. It has been established that efficient recombination can be accomplished during reverse transcription by a mechanism in which RT initially reverse transcribes one viral RNA, but then especially in regions of breaks, switches to another RNA

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template, resulting in high-frequency recombination (Fig. 2B). Thus, the process of reverse transcription is a major contributor to retrovirus variation. However, reverse transcription itself is also responsible for a high level of nucleotide misincorporation because it lacks proofreading activity. Hence, clear molecular grounds exist for high retrovirus variability, which is a prerequisite for their great genetic plasticity manifested by an array of pathogenic consequences, including those that arise by successful retrovirus heterotransmissions (see later and discussion in later chapters). RT uses retroviral genomic RNA to synthesize viral DNA, but it can also employ templates consisting of transcripts of cell genes. This has made it possible for retroviruses to acquire cellular sequences, including those that are responsible for cell transformation. These gene sequences, called oncogenes, constitute spliced versions of normal cellular genes that perform various vital cell functions (see Fig. 3). Collectively, they are called proto-oncogenes (c-onc), which, however, does not give an account of their normal activities. According to the generally preferred and likely scenario, a retrovirus first integrates in front of a proto-oncogene and takes over proto-oncogene expression through its strong promotor-enhancer signals located in the LTR. Once the proto-oncogene LTR-driven transcript is incorporated into the virion together with viral RNA, it can acquire additional retroviral sequences,

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combination of two oncogenic a c t i v i t y _ j ) Fig. 3 M a i n ways by which proto-oncogenes are reshaped into oncogenes. For details, see text. E-enhancer, shaded rectangles, a proto-oncogene. Mutations are denoted by a black vertical m a r k and unrelated gene sequences by a checkered pattern.

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located especially at the 3' end, by recombination in the course of reverse transcription (Fig. 2B). Thus, exons of a proto-oncogene can be incorporated into a retroviral genome, where they become transcriptionally activated by the LTR. In most cases, however, oncogene formation requires additional specific mutations, the occurrence of which is facilitated by errors occurring during the course of RT-mediated DNA synthesis. Nonviral oncogenes (Fig. 3) can be activated in a similar manner if they are translocated into the vicinity of strong cellular promotor-enhancer sequences and/or mutated in critical regions. Oncogenes can also be activated by amplification of their structure or by fusion with other unrelated genetic elements that will profoundly alter their function and/or ensure ectopic expression. Certain oncogenes such as m y c and ras can efficiently complement each other and in conjunction act as a more oncogenic stimulus. This is an overall picture, but we have to take into account that the oncogene activity is also modulated by the functional state of the target cell, which includes cell cycling exposure to signal transmitters, differentiation, etc. That the type of target cell plays an essential role in cell transformation with a viral oncogene has been exemplified by the lack of oncogene v - s r c - m e d i a t e d transformation of human cells, in contrast to rodent cell transformation (Hjelle et al., 1988), and the finding that in RSV-infected chickens, tumors arise at the sites of injury, thereby mobilizing cytokines such as TGF-fl and inducing supportive stroma formation (Sieweke and Bissell, 1994). It should be stated clearly that not only acutely transforming retroviruses that have acquired (or transduced) oncogenes, but also nonacutely transforming retroviruses lacking an oncogene can produce tumors, although with a long latency. After several months of replication in an organism, there is a possibility for either oncogene transduction or integration in the vicinity of a proto-oncogene, which leads to its activation either by the retrovirus promotor-enhancer effect or even over a larger distance by LTR enhancer activity. Needless to say, the outline presented here covers only the basic strategies employed for oncogene activation, as a description of the specific features of essentially every oncogene would exceed the scope of this review. Finally, it should be pointed out that oncogenes not only trigger cell transformation, but are also required for maintenance of the transformed state. Direct evidence has been provided by conditional trangenesis, in which oncogenes such as m y c or ras were placed under the control of a regulatory element that makes it possible to switch off oncogene expression. Both m y c and ras downregulation at the stage when they produced lymphoma or melanoma, respectively, led to rapid tumor regression accompanied by apoptosis (Chin and DePinho, 2000). These and other observations support the view that oncogenes should be considered primary targets for therapeutic procedures consisting of selective gene inhibitors.

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III. CHANGES IN RETROVIRUS ONCOGENIC AND PATHOGENIC POTENTIAL BY SELECTION, MUTATION, AND RECOMBINATION A. Increasing Retrovirus Replication The significance of virus selection for establishing an efficiently transforming retrovirus was already recognized in the case of the original Rous sarcoma virus (RSV) isolated from chicken, which over the years has been a principal tool for defining retrovirus replication, molecular biology and the first retroviral oncogene v - s r c . Before it was proved that this sarcoma contains filterable virus (Rous, 1911), it had been passaged as a tissue suspension. Successful transmission was obtained only in rare cases, in particular when using animals from the breed in which the original sarcoma arose (Rous, 1910). It is impossible to know the extent of changes produced in RSV after almost a century of passaging, but recombination with ALVs contributed to its diversification, including acquisition of new host-range properties directed by ALV subgroup specificities (Wang and Hanafusa, 1988). Later, Bryan e t al. (1955) demonstrated that sarcomas containing high amounts of transforming RSV again induce i n v i v o tumors rich in transforming virus, and he selected high-titer RSV called Bryan high-titer RSV (BH RSV). Such an RSV strain fulfilled the criteria for a highly infectious retrovirus suitable for the investigation of i n v i t r o - t r a n s f o r m i n g activity. We mention these historical observations to illustrate the general notion that laboratory retrovirus strains underwent repeated passages, which have led to the accumulation of changes, thereby increasing the retrovirus replicative potential.

B. Acquisition and Activation of Oncogenes In connection with the discussion of RSV, it should be stressed that this virus, as well as other acutely transforming retroviruses, acquired the exons of the normal cell c - o n c gene, in this case c - s r c (see Section II). In the course of recombination with a retrovirus, c - s r c had been truncated at the carboxy end of the last coding exon, which led to its reshaping into the oncogene v - s r c . Both c - s r c and v - s r c code for protein tyrosine kinase (PTK), a prototype of Src family PTKs, which couple signal transduction at the cytoplasmic face of the cell membrane. In addition to nondefective RSV strains (see Section I), v - s r c has been acquired in the case of several viral isolates at the expense of ALV replicarive genes, which led to the formation of replication-defective virus strains.

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As shown in Fig. 4 (see color insert), in BH RSV the e n v gene was substituted by v - s r c . A different picture was encountered in two acutely transforming v - s r c - h a r b o r i n g viruses isolated from sarcomas that appeared in ALV-Ainfected chickens (Ikawa e t al., 1986). The S1 virus consists of v - s r c followed by the deleted e n v gene, and the $2 virus contains v - s r c flanked with deleted g a g on one side and p o l on the other side (Fig. 4). In both cases--similar to RSV--the carboxy end of the v - s r c coding region, including the regulatory tyrosine 527, was truncated, with addition of a region coding for anomalous amino acids. A new strategy for how c - s r c can be reshaped to form v - s r c is provided by the PR2257 acutely transforming retrovirus (Geryk e t al., 1989) isolated from a sarcoma that appeared after inoculation of ALV-C in chickens. As depicted in Fig. 5 (see color insert), PR2257 is composed of a proviral structure similar to $1 (Fig. 4). In contrast to other v - s r c - h a r b o r i n g viruses, recombination between the retrovirus and c - s r c was not accomplished in PR2257 at the end of the last c - s r c coding exon, but further downstream in the region of a noncoding exon. Despite the fact that this region is not translated, it is transcribed and constitutes the terminal part of c - s r c mRNA called the 3 ~end c - s r c - u n t r a n s l a t e d region, abbreviated 3'UTR. (3~UTR has been identified in many mRNAs as a very important regulatory domain profoundly influencing several posttranslational events. Despite being well represented in c - s r c mRNA, its function remains elusive.) However, a single mutation appeared in PR2257, produced by a cytosine insertion at the 3' end of its last coding exon, which led to a change of reading frame accompanied by substitution of its terminal amino acid and extension of the reading flame for a total of 62 new amino acids. Hence, not only truncation but also the change of reading flame can activate c - s r c to v - s r c . The PR2257 virus also exemplifies the instability of the genome structure of freshly isolated virus. It was found that the original virus isolates replicated very poorly, and therefore to increase virus titers, the virus was passaged repeatedly in chickens. After 16 tumor transfers, its transformation activity increased by at least 10-fold, concomitant with a loss of two potentially c i s - a c t i n g negative elements, such as an unusual translation initiation codon and a significant part of the 3~UTR (Fig. 5) (Yatsula e t al., 1994). Genome reshaping has probably been involved in the acquisition of high-titer replication in previously isolated acutely transforming retroviruses, but due to a lack of relevant techniques, they went unnoticed. Both c - s r c and v - s r c were reviewed exhaustively by Thomas and Brugge (1997) and then by Martin (2001); the involvement of the s r c gene product in cell signaling has been discussed by Abram and Courtneidge (2000) and Schlessinger (2000). It should be noted that not only functional c-Src domains, but also their three-dimensional structure and ways of their mutual interaction have already been established. We shall therefore provide an overview without extensive referencing and concentrate on the main issues

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and unresolved problems. To present the essential structural and functional features, we show a simplified, two-dimensional scheme (Fig. 6A, see color insert). The product of both c - s r c and v - s r c is a protein tyrosine kinase, which phosphorylates proteins on tyrosine residues. In a cell, this kinase is anchored at the inner face of the cell membrane by its amino-terminal myristylated variable region. Then follows the SH3 (Src homology 3) domain, which exerts the protein-binding activity through polyproline-rich motifs. Next is SH2 (Src homology 2), followed by the PTK catalytic domain. Finally, the carboxy end represents the regulatory domain highlighted by tyrosine (at position 527). When phosphorylated, tyrosine 527, together with several neighboring amino acids, binds to the SH2 domain, producing the initial conformational change (Fig. 6B). The second conformational change is made possible by the SH3 domain binding to the linker region (Fig. 6A). These structural changes result in displacement of the o~C helix in the catalytic domain, depriving this domain of required autophosphorylation, which leads to downregulation of the PTK activity reaching the normal physiological level. The oncogene v - s r c arises by substitution of the c-Src carboxy end with other unusual amino acids. Of key importance is the loss of tyrosine 527, which acts as the main player in the events leading to the first step of c-Src PTK downregulation mediated by the regulatory domain binding with the SH2 domain. Thus, Tyr 527 absence allows for constitutive PTK activation (Fig. 6C). We should take into account that additional amino acids surrounding tyrosine 527 can also influence c - s r c downmodulation. Deletion or substitution of the critical tyrosine 527 occurred in all known cases of v - s r c transduction by a retrovirus. However, additional mutations, e.g., in SH2, SH3, or even in the adaptor region, endow c - s r c with a different degree of cell transformation activity. A series of independent studies have demonstrated that v - s r c , even in the form of cloned naked DNA, induces fast-appearing sarcomas in chickens (Svoboda, 2000), and the best estimates suggest that at least one out of about a hundred v - s r c - e x p o s e d cells became transformed (Stoker and Sieweke, 1989). It should be taken into account that additional genetic changes, such as activation of antiapoptotic signals and/or cell immortalization, are required for v - s r c - m e d i a t e d tumorigenesis. However, a high v - s r c tumorigenic and transforming activity suggests that this oncogene should have the capacity to engage antiapoptotic genes and the cell survival signaling pathway, as has been documented clearly (Fig. 7). Because sarcomas that develop after v - s r c inoculation occur in chickens within 10 days, secondary genetic changes responsible for immortalization should either appear quickly or are not required for primary tumor outgrowth. That cell immortalization need not be involved is suggested by the finding that primary tumor tissues are not readily transplantable in syngeneic birds. Furthermore, data have been obtained indicating that the immortalization of chicken cells is not accompanied by

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activation of antiapoptotic bcl-2-related gene Fig. 7 Illustration of some principal signaling pathways that can be activated by v-Src. The main signaling pathway is drawn schematically as a solid arrow. For further information about the role of Src in signal transduction and the molecular events influencing its tyrosine phosphorylation activity, see Abram and Courtneidge (2000) and Hakak et al. (2000). Nuclear proto-oncogene activation and the elements involved in it are summarized according to Curto et al. (1997). SRE, serum response element; TPA, 12-O-tetradecanoylphorbol-13-acetate response element; CRE, cAMP response element. The proto-oncogene myc-activating pathway (see text) is illustrated as a dashed vertical arrow. On the right side, the pathway resulting in phosphoinositide-3-OH kinase (PI-3 kinase) (through its SH-2 domain) and protooncogene A k t (PKB) activation is given. For this pathway, the adapter protein Cbl and protein tyrosine phosphatase (Shp-2) are required (Hakak et al., 2000). The oncogene v-src also activates, especially phospholipase D (PLD) (Jiang et al., 1995), and second messengers then trigger the protein kinase activity of some PKG isoforms (Zang et al., 1995), which could reinforce file main signaling pathway leading to cell proliferation and also contribute to cell transformation. Src involvement in other cell signaling events is referenced in Svoboda (2000) and those mediated by focal adhesion kinase (FAK), Stat3, and immortalization are discussed briefly in the text.

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a set of molecular events previously recognized in mammals, such as activation of telomerase and extension of the telomere size, but that it is linked to p53 downregulation and Rb pathway upregulation (Kim e t al., 2001). Thus, regulatory changes in tumor supressor genes might play a role in the longterm survival of chicken cells. A further extension of these findings, as well as additional quantitative cell transformation and cell tumorigenicity studies aimed at the contribution of secondary genetic changes to v - s r c oncogenesis, especially in relation to cell immortalization, is required. Despite very detailed knowledge of the c - s r c and v - s r c PTK structure and its activation, we are still lacking a full picture of v - s r c involvement in signal transduction pathways and their dysregulation. As summarized in Fig. 7, v - s r c potentiates the main signaling pathway leading from receptors of growth factors to cell proliferation. There are, however, several other points at which v - s r c may augment different cell signaling branches. In addition to cell proliferation, v - s r c acts as a mitogen and triggers the antiapoptotic response. More recently, it has been established (1) that Star protein family members couple signal transduction from cytokine receptors and tyrosine kinases and (2) that translocation of dimerized Star molecules to the nucleus promote cell cycle progression and/or cell survival (Bowman e t al., 2000). Importantly, blocking Star3 abolishes v - s r c transformation. Src PTK is actively engaged in integrin signaling, especially in specific phosphorylation of focal adhesion kinase (FAK). FAK not only modulates the cell shape and behavior via adaptor proteins, but also manages to strengthen the main signaling pathway activating proliferation and transformation and, through the activation of proto-onc0gene Akt, also cell survival and additional antiapoptotic genes (Schlaepfer and Hunter, 1998; Schlaepfer e t al., 1 9 9 9 ; Webb e t al., 2000). Src, as well as the PTK Src family, intervenes with a series of further signaling events, which may not necessarily be associated with cell transformation, but can be required for tumor progression, e.g., vascular endothelial growth factor (VEGF)-mediated angiogenesis (Eliceiri e t al., 1 9 9 9 ) . Therefore, a general picture of v - s r c action appears to be nebulous and complicated, but what can be expected from a molecule cross-connecting a series of vital processes? Needless to say, we require extensive insight into various facets of c - s r c and v - s r c engagement in cell functions in order to delineate the interplay of determinants of v - s r c tumorigenic activity. We should finally comment on the possible involvement of v - s r c in the genesis of human tumors (Irby and Yeatman, 2000) and in the development of therapeutic strategies based on this knowledge of oncogenes. Activation of c-Src PTK has been encountered in many human tumors, such as breast carcinomas, colon carcinomas, pancreatic cancers, and others. This increase may be a consequence of c-Src PTK interaction with other targets, especially with receptors of growth factors, but also might be a consequence of decreased tyrosine 530 (human equivalent of chicken tyrosine 527) phosphorylation by

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the corresponding kinase (Csk) or its dephosphorylation by a phosphatase (Bjorge et al., 2000). It appeared that truncation of the c-Src carboxy end, which had been shown to be a decisive step in reshaping chicken c-src to v-src, also occurred in a subset of metastasizing colon carcinomas. Hence, modulation of the c-Src PTK activity, and in some cases also alteration of the c-src structure, can play a role in different human cancers, but in contrast to the situation in chickens, a strongly transforming src-based oncogene has not been revealed in humans. The function of the proto-oncogene c-src PTK as an important signaling molecule is secured by additional members of the Src PTK family, namely c-Yes and c-Fyn, which complement its normal function (Stein et al., 1994). Once c-src but no other member of the PTK family is activated in a tumor, then various agents such as antisense oligonucleotides or specific PTK inhibitors, directed against c-Src, should inhibit its cancer-associated activity, but not disturb its physiological activities. These activities can be assumed by other Src PTK family members. Hence, highly complemented and secured src functions do not represent an obstacle for therapeutic interventions, but rather provide a suitable target. Another oncogene that has attracted general interest, especially because its cellular counterpart was shown to participate in the genesis of some human tumors, is the oncogene v-myc. It was recognized as a part of several avian acutely transforming retroviruses that induce tumors by transforming bone marrow cells in the myelomonocytic stage of differentiation. However, v - m y c has also a general propensity to transform fibroblasts. The field of myc, booming in the 1980s, has been reviewed by Lee and Reddy (1999), who also provide a complete list of relevant citations. Acutely transforming myc-containing viral strains usually acquired the oncogene as part of the Gag-Myc fusion protein. In some cases, gag gene sequences contribute to transformation, possibly due to the presence of enhancers in this region. The essential role ascribed to v - m y c was the stimulation of cell proliferation (Lemaitre et al., 1996), and the experimental evidence obtained so far suggests that additional steps in transformation, such as anchorage independence and cell immortalization, probably result from m y c - i n d e p e n d e n t additional genetic changes. As a cell proliferation-stimulating gene, m y c efficiently complements other oncogenes, such as ras or even src, and it has been detected in the Mill Hill endothelioma virus (MH2), which contains the additional oncogene v-rnil, the equivalent of the mammalian oncogene v-raf. Such a two-oncogene tandem has an increased efficiency for cell transformation and can also transform terminally differentiated neuroretinal cells (B~chade et al., 1985,1988). Of course, rnyc overexpression, mediated efficiently by retroviral LTRs or other enhancer elements located in the vicinity to which c-myc translocates, is of principal importance. Furthermore, species-specific factors modify the oncogenic activity of v - m y c mutants, with

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some of them being effective in Japanese quail cells, but not in chicken cells (Biegalke et al., 1987). In contrast to v-src, no single critical change is known in c - m y c leading to its reshaping into an oncogene. Both c - m y c amino-terminal (transregulatory) and carboxy-end (basic-helix-loop-helix-leucine zipper) domains are embodied in v-rnyc, but additional mutations in these regions, including tissue specificity, potentiate and/or modify its transforming activity, tissue specificity included. Hence, there is a gradient of oncogenic potentials increasing from c-rnyc through chimeric constructs to v-myc. Again, no simple way exists to explain how the m y c gene intervenes in the cell functions. The nuclear transactivator rnyc gene product must first heterodimerize with additional related proteins. Depending on the partner protein, it either activates or represses a series of cellular genes. The partner protein Max forms MycMax heterodimers attaching to a DNA motif called E, where they entail further protein-protein interactions, resulting in the mobilization of histone acetylase and, in turn, gene activation. Conversely, heterodimerization with Mad yields an opposite effect, which in the final step triggers deacetylation (Eisenman, 2001; Liibscher, 2001). It is known from many other studies that the degree of histone acetylation in general correlates positively with gene expression. Accordingly, Myc-Max activates not only genes involved in the cell cycle and proliferation, but also affects other cell functions, such as those responsible for apoptosis, survival, and metabolism. Thus, m y c targets are multiple, and those required for cell transformation remain to be defined. Such a multifaceted engagement of rnyc reminds us of a similar complex situation encountered in src, despite the fact that the former is a nuclear transcriptional regulator and the latter a cytoplasmic signaling molecule. This has an implication in the course of overexpressed c-rnyc-induced lymphoma genesis, where not only B-cell expansion, but a block of their differentiation, including emigration from lymphoid tissues and stimulation of angiogenesis, play an important role (Brandvold et al., 2001). Why v - m y c is a generally encountered oncogene has not yet been clarified. This problem has been approached by taking into account rnyc translocation in the vicinity of the immunoglobulin gene that triggers B-cell lymphoma genesis in Epstein-Barr (EB) virus-infected humans in Africa. As suggested by Klein (2000), this translocation, as well as other lymphoma-associated translocations (Davila et al., 2001), could be facilitated by the RAG transposase activity governing recombination and resulting in variation of the immunoglobulin locus [V(D)J] (Roth and Craig, 1998; Hansen and McBlane, 2000). It has been reported that the DNA-dependent protein kinase (DNA-PK), which allows repair of double-stranded DNA breaks, is required for sealing DNA ends during retrovirus integration and RAG transposasemediated V(D)J recombination (Daniel et al., 1999). Because DNA-PK probably interacts with RAG proteins, this complex might create a region

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suitable for retrovirus integration due both to the presence of DNA breaks and to the capacity to join DNA fragments. Moreover, additional unique properties of chicken B cells might play a role. Among these properties is the ability to ensure efficient homologous recombination with transfected DNA, which might be related to the RAG transposase activity and/or to activation of cell functions involved in DNA alignment and repair of especially DNA double-stranded breaks (Buerstede and Takeda, 1991; Sonoda et al., 2001). Thus, there are some hints that are helpful for understanding the c-myc propensity to translocate and to be transduced by a retrovirus. Despite the fact that the proposed mechanisms remain hypothetical, they illustrate that more knowledge about the molecular mechanisms of retrovirus integration and proto-oncogene translocation should provide a more concise picture of acutely transforming virus genesis. Apart from older observations, new data document the fact that myc is transduced efficiently by ALV-unrelated REV and that the newly defined highly pathogenic recombinant ALV-J regularly acquires gag-myc sequences and becomes an acutely transforming virus (Noori-Daloii, 1981; Chesters et al., 2001).

C. Viral Genome Alteration and Pathogenicity A high degree of retrovirus defectiveness need not always be associated with an oncogene transduction, but can also result in new pathogenic properties. This was disclosed in the case of LP-BM5 MLV isolated as a virus mixture from radiation-induced lymphoma by Latarjet and Duplan (1962), which produces MAIDS characterized by hypergammaglobulinemia, splenomegaly, lymphadenopathy, and dysfunction of T and later B cells, marked by susceptibility to opportunistic infections and finally also by B and/or T lymphoma formation (Jolicoeur, 1991; Morse et al., 1992; Liang et al., 1996). The highly defective BM5 virus, coding for the unprocessed, truncated, and mutated gag precursor product, is responsible for the immunopathogenicity of the LP-BM5 virus mixture. The nature of BM5-triggered immunodeficiency has not been elucidated, and there have been several reinterpretations, including the hypothesis that the BM5 product could act as a superantigen. Being a mouse disease, MAIDS studies profit from immunologically wellcharacterized mouse strains, including mice lacking both alleles of certain important genes that modulate the immune response (designated as knockout, KO). More recently, these approaches have offered some more conclusive insights into the set of events leading to MAIDS. Of main importance is the interaction between T and B cells, accomplished by a T-cell ligand interacting with the B-cell membrane signaling protein (CD40). Such interaction proceeds in MAIDS in an abnormal fashion, leading to B- and CD4 + T-cell activation, hyperproliferation, and finally to B-cell anergy. However,

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the chain of events commences with CD4 + T-cell infection and anergy because in the absence of CD4 + T cells, no changes in the B-cell population appear (Simard et al., 1997; Green et aL, 2001; Harris et al., 2001). Despite defining the immunological parameters of MAIDS, we still lack an understanding of how the BM5-crippled Gag precursor protein intervenes with CD4 + T-cell functions and their interaction with B cells. There remains a highly speculative possibility that the abnormal gag product might act as a molecular mimic or unusual protein exceptionally suited for modifying essential immunological reactions. The still nebulous state of understanding MAIDS, despite a preference to use the most advanced mouse experimental model, reminds us that one should proceed with caution in interpreting the intriguing complexity of retrovirus-induced immunodeficiency. The exact delineation of retrovirus sequences responsible for certain pathological changes has been, in some cases, as yet unsuccessful. This is the case of avian osteopetrosis characterized by bone thickening produced by some ALV strains (see also Section V). Several parts of the ALV genome, such as noncoding sequences upstream from the 3' LTR and the gag-pol-5'env region, were initially thought to be involved (Robinson et al., 1982; Shank et al., 1985). According to a series of additional investigations, several genome regions play an important role, including env (subgroup B or E), LTR, and a noncoding region downstream from the 5' end LTR spanning the leader region required for the function of viral mRNAs (Robinson et al., 1986, 1992; Brown etal., 1988; Aurigemma etal., 1991; Joliot et aL, 1993). Therefore, some set of changes, probably scattered through different genome regions, is required for virus pathogenesis. This example offers a good bridge to the even more complicated problem of genetic changes related to SIV pathogenicity, as SW has become the animal model most related to HIV infection. As discussed in Section VII, several SIV strains produce immunodeficiency when heterotransmitted to some other primate species. There is no doubt that the SIV as well as the HIV genome are prone to sequence variation (see Section II; Coffin, 1995). Therefore, we wish to introduce some findings documenting SW sequence changes and their impact on the pathogenic consequences produced in heterologous hosts. In monitoring virus variants appearing in the course of cloned SIV infection, viruses replicating with high efficiency were isolated and found to have an altered Env glycoprotein that escapes virus neutralization antibodies (Kinsey et al., 1996; Chackerian et aL, 1997; Hirsch et al., 1998a; Holterman et al., 1999; Kimata et al., 1999) or cytotoxic T lymphocytes (Mortara et al., 1998; Allen et al., 2000). In addition, SW variants with expanded coreceptor usage or producing syncytia were reported (Rudensey et al., 1998), as well as recombinants selected out by acquisition of a missing accessory gene (Wooley et al., 1997). This chapter provides several sequentially analyzed examples documenting the complexity of SIV genome modification and the effect on the degree of

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SIV pathogenicity. A series of interesting differences between nonpathogenic and pathogenic SIV strains have been made. In molecular cloning of the SIV genome, nonpathogenic clone 1 A l l was isolated and compared with the progeny of a pathogenic clone. A sequence difference between the two strains comprised about 200 bp, which in the case of the attenuated virus included new stop codons in vpr and env (TM). The biological significance of these and additional mutations was studied by the construction of recombinants between both viruses, with exchange of different genome portions. The results obtained provided an interesting picture, indicating that attenuation is a quantitative genetic (polygenic) feature and, therefore, the symptoms of pathogenicity, such as persistent viraemia and finally AIDSlike disease, have been enhanced with a higher amount of pathogenic viral sequences in the recombinant (Marthas et al., 1993). Later, a more straightforward way for depicting the critical changes was employed. It was based on the characterization of pathogenic revertants that appeared in the 1 A l l mutant population. Using this short-cut approach, it was possible to characterize the changes leading to the reemergence of virus pathogenicity. It turned out that pathogenic revertants reacquired the env gene TM portion lost in the 1 A l l mutant. The significance of this change was confirmed in reconstruction experiments, in which multiple mutations were introduced in the TM of pathogenic SIV, abolishing its pathogenicity even for neonate macaques (Luciw et al., 1998; Shacklett et al., 2000). However, viruses with crippled TM reproduce less efficiently in vivo, which might contribute to their nonpathogenicity. Another attempt to define SIV pathogenic determinants was again based on the study of the recombinant virus, which had acquired the 3' end half from the pathogenic virus and so retained a highly pathogenic phenotype. Again, multiple changes (62 mutations), which also led to elongation of the env and nefgene products, have been observed (Edmonson et al., 1998). Thus, a number of experiments demonstrated that different parts of the viral genome were of importance for virus replication and pathogenicity (Kimata and Overbaugh, 1997; Kimata et al., 1998). A special lesson was learned from SlVsmmVBj14(abbreviated PBj 14), which is acutely pathogenic for pig-tailed macaques (Fultz et al., 1989). It is fatal for infected monkeys after about 10 days due to symptoms of diarrhea accompanied by extensive T-cell activation and apoptosis in gut-derived tissue, rather than from immunodeficiency. As reconstructed later, PBj 14 arose not in one step, but as a result of a sequential series of mutational changes in SIVsm heterotransmitted to macaques, where it became a variant endowed with a dominant phenotype (Tao and Fultz, 1995). In addition to subtle mutations, this isolate harbors a duplicated NFKB transcription factor-binding site (Dewhurst et al., 1990). Knowledge of the PBj14 genome provided an opportunity to test the significance of some individual coding changes. Interest has been focused on the accessory nef gene. The Nef protein fulfills several functions, but is also active, in a myristylation-dependent manner, in

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the cytoplasm, where it interacts with various proteins, including those having serine/threonine kinase activity (Subbramanian and Cohen, 1994; Sawai et al., 1995) or belonging to the Src family PTKs (Saksela et al., 1995). This raises the possibility that Nef may interact with signaling pathways. This possibility was supported by experiments in which several amino acids, including two critical tyrosines, in the accessory nef gene of SIV were modified according to the pattern known from PBj14 (Du et al., 1995). Thus, an acutely pathogenic virus arose containing a new motif capable of binding the SH2 domain, which is widely employed in cell signal transduction, especially in the case of the Src family of PTKs. This new motif, as reported more recently, mimics the immunoreceptor tyrosine-based activation motif (ITAM) present on the { chain of B- and T-cell receptors and is required for the antigenic stimulation of lymphoid cells. As understood so far, two tyrosines in ITAM must first be phosphorylated by Src family PTK, especially by Lck, which was shown to interact specifically with the Nef protein (Collette et al., 1996; Baur et al., 1997) and which results in Lck activation (Greenway et al., 1999). This makes it possible for SH2 domains of ZAP-70 PTK to couple with phosphorylated tyrosines, which also takes place in the course of T-cell antigenic stimulation (Fig. 8). Thus, an unusual ITAM motif, which occurs in Nef, acts as a constitutive stimulator of T-cell activation and

Lck mediated Y phosphorylation facilitated by SH3 Lck domains

and

SH2

Fig. 8 Essential steps in signaling of the ITAM motif present in the accessory pBJl4 strain, modified according to Luo and Peterlin (1997). For explanation,

T cell activation proliferation gene nefof see text.

the

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proliferation (Luo and Peterlin, 1997) and also apoptosis (Gummuluru et al., 1996; Saucier et al., 1998). Other consequences result from the coupling of Nef with the ~ chain of the T-cell receptor (Bell et al., 1998). One example is the upregulation of Fas ligand expression, requiring the ITAM motif and favoring T-cell apoptosis (Hodge et al., 1998; Xu et al., 1997, 1999). Furthermore, an association of nonmutated SIVmac,SIVsm,and HIV-2 Nef with the g chain was revealed (Howe et al., 1998), suggesting more general Nef involvement in TCR ~"chain signaling. Because the Nef product represents a highly dynamic molecule, its conformational changes and mode of interaction with the cell membrane should alter Nef activity significantly (Arnold and Baur, 2001). This could explain, at least in part, some controversial findings obtained with HIV-1 Nef (Renkama and Saksela, 2000; Hanna et al., 2001). As usually encountered in signaling pathways, additional factors are in play. One of them, the Nef-associated serine-threonine kinases (NAK) (see earlier discussion), which couple with Nef through the SH3 domain or another region, were also implicated in the stimulation of T-cell signaling (Manninen et al., 1998; Xu et al., 1999), but this interpretation was not universally accepted (Lang et al., 1997). However, not every SH2- or SH3-binding motif found in the virus protein needs to have an effect on SIV biology, as demonstrated in more recent studies (Carl et al., 2000). Moreover, there is a disagreement about the nefgene function in SIV strains other than PBj 14, especially its involvement in lymphoid cell activation vs cell inhibition. Arguments favoring the first interpretation were discussed more recently by Alexander et al. (1997) and the second interpretation by Iafrate et al. (1997). The significance of the ne[ accessory gene for SIV and HIV replication and pathogenesis goes beyond the subject of this section, but it should at least be stated that Nef plays an important role in ensuring virus replication in lymphoid cells in vivo and producing immunodeficiency in mice made transgenic by inoculation of the nef gene driven by the T-cell-specific promoter-enhancer. We mention these findings in more detail because they unveil the intimate interactions of SIV/HIV with host-cell signaling, suggest that such interaction can decide the outcome of infection, and help understand mutations in a broader context with cell-signaling pathways. These and additional data (Hanna et al., 1998) also point to an important role of nef (Kestler et al., 1991; Whatmore et al., 1995; Khatissian et al., 2001) and both vpr and vpx (Hirsch et al., 1998b; Gibbs et al., 1995) accessory genes in ensuring high viral loads and producing apparent pathogenic consequences. Comparative studies making deletions (either singly or in combination) in these viral genes and in other SIV genome regions and their combination pointed to the conclusion that the greater the number of genomic regions inactivated, the lower the degree of virus replication. Again, for pathogenicity, a certain critical level of virus replication is required. After inoculation of

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viruses bearing deletions, protective immunity against intravaginally applied pathogenic SIVmacwas detected; however, the degree of this immunity decreased as virus replication was reduced (Desrosiers et al., 1998; Johnson et al., 1999). Not surprisingly, there is no simple interpretation of specific motif involvement in the virus pathogenicity. Thus, based on testing the chimeric viruses that were constructed by exchanging different pathogenic PBj 14 clones with related nonpathogenic SIVsm, the conclusion was reached that the critical determinant of pathogenicity lies in the env gene. Multiple effects of other genes, including gag-pol and especially nef (Novembre et al., 1993, 1996) were also observed. In comparing virus strains related evolutionarily to PBj14, it was inferred that PBj14 high pathogenicity is a multigenic trait and that n e f m u t a t i o n is responsible for resting lymphocyte proliferation, but not for other disease manifestations (Tao and Fultz, 1999). Similarly, a follow-up of a chimeric construct that acquired PBj 14 nef again revealed only in vitro stimulation of resting peripheral blood mononuclear cells in the absence of in vivo pathogenicity (Schwiebert et al., 1997). That the issue of PBj14 exuberant pathogenicity relates to a set of modifications was brought up very recently, when one highly pathogenic and one minimally pathogenic viral clones were compared (Haddrick et al., 2001). The strains differed in one amino acid substitution in both Vpx and Nef and in three in Env. One of the Env amino acid changes found in the low pathogenic clone was shown to be responsible for a decrease in infectivity and abrogation of pathogenicity when introduced in the highly pathogenic clone. However, the minimally pathogenic clone could not have been remodeled to the high pathogenic phenotype just by acquiring the critical amino acid mutation from the latter one. A series of reports therefore favor the possibility of the involvement of multiple genetic changes in SIV pathogenicity, which more specifically include the accessory gene nef and, not surprisingly, the env gene as well. Because the number of coding changes in question has now been reduced to six, we may soon gain an account of critical mutations and their combination responsible for the high PBj14 pathogenicity. Important achievements were accomplished in pursuing the pathogenicity of the chimeric virus called SHIV, based on SIV, in which the env gene and three accessory genes (tat, rev, and vpu) of HIV origin were inserted. This viral hybrid behaved originally as a nonpathogenic strain, producing a low level of persistent infection in macaques. However, repeated passages led to isolation of pathogenic SHIV strains. The critical change responsible for acquired pathogenicity was ascribed to two mutations in the SHIV env gene and correlated with a high fusogenic activity and cytopathic activity in CD4 + T cells (Etemad-Moghadam et al., 2001). Despite the fact that we do not cover feline leukemia viruses (FeLV), we should at least note that

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immunodeficiency-producing mutants exhibiting features similar to PBj14 were isolated from nonvirulent FeLV (subgroup A) (Donahue et al., 1991). In such feline virus strains, several amino acids were inserted in a particular region of the e n v gene, which increased either the fusogenic activity or T-cell tropism due to the use of a coreceptor expressed efficiently in T cells (Rohn et al., 1998; Anderson et al., 2000). This provides an additional independent argument in favour of e n v gene modification as a critical factor in triggering immunodeficiency. Analysis of sequence differences between nonpathogenic and simian AIDSproducing SIV variants has not so far provided the answer to the question: "What critical changes are responsible for the outcome of infection?" Most likely, SIV pathogenicity results from alteration of a few viral genes and regulatory elements. In many of the aforementioned papers it was stated that pathogenic SIV strains replicate more efficiently, a possibility supporting the notion that both efficient virus replication and pathogenicity are interrelated and that there is some critical threshold of efficiency of virus replication that determines virus pathogenicity (Ruprecht et aI., 1996b). Despite being attractive, this idea remains to be verified. In retrovirus infections in general, the virus should be replicated to certain levels to produce overt pathogenic effects. However, the pathogenicity itself is not just a result of the high viral load, but is usually dictated by the properties of the viral genome-coded products and the host cell. In other words, known retroviruses, such as avian ALV subgroup A, replicate in vivo to high titers and recombine efficiently with oncogenes, but are devoid of pathogenic activity in contrast to other ALV subgroups. In the case of SIV, introduction of additional transcriptional factor-binding sites, such as Spl and NF~cB, enhances early virus replication in the absence of augmented pathogenicity (Edmonson et al., 1998). The deletion in both these elements did not abrogate SIV pathogenicity (Ilyinskii and Desrosiers, 1996; Ilyinskii et al., 1997). Furthermore, there is a plethora of data, documented later (Section VI), showing that in its natural host, SIVs infect various cell targets effectively and the viral load is comparable to that encountered in heterologous monkey species succumbing to an AIDS-like disease. Thus, the essential problem of SIV pathogenicity remains to be solved.

IV. RETROVIRUSES FROM WITHIN In discussing retrovirus pathogenesis, we should mention not only exogenous retroviruses, which infect different hosts, but also endogenous retroviruses integrated in all germinal cells and inherited in the same Mendelian way as normal genes. Endogenous retroviral elements were defined in

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chickens on the basis of the fact that some chicken strains have been found to synthesize the g a g or e n v gene products that correspond serologically to those known from ALV and that could also have complemented (in trans) the defects in the corresponding ALV genes. Thus, right from the beginning, this enigmatic situation underwent several changes in interpretation and was finally clarified by the discovery of RAV-0, an infectious retrovirus whose proviral form was integrated into the germ line cells of certain chicken strains (Svoboda, 1986; Crittenden, 1991). Great progress was made in rodents, especially in mice, where several types of endogenous viruses have been characterized. Among them, ecotropic retroviruses possess the MLV env, allowing infection of only murine cells, in contrast to xenotropic viruses, which infect only heterologous cells. In addition, dual-tropic (or polytropic) viruses are transmissible to both routine and heterologous cells. The series of recombination events among ecotropic, xenotropic, and dual-tropic viruses could have resulted in the formation of oncogenic retroviruses causing thymic lymphomas in mice by activating proto-oncogenes. Moreover, another tumorigenic murine virus, mouse mammary tumour virus (MMTV), is integrated into the germ line of some mouse strains. Under proper conditions it can be expressed and, when inserted into the vicinity of two critical proto-oncogenes, it triggers mammary adenocarcinoma genesis (Boeke and Stoye, 1997). In contrast to mice, avian endogenous retroviruses closely related to RAV-0 (called the ev loci because they are integrated in a certain position in chromosomal DNA like other normal loci) and RAV-0 itself were found not to be pathogenic. Furthermore, chicken breeds free of e v loci were outcrossed and resulted in no developmental abnormality (Astrin et al., 1979). Due to these findings, interest in ev studies decreased, but a new impetus was provided by Resnick et al. (1990) and Boyce-Jacino et al. (1992), who discovered a more ancestral viral group called endogenous avian retroviruses (EAV), highly conserved in the avian genus G a l l u s . The domestic chicken is one member of this group. EAV are amplified (about 50 copies per genome), usually lack the surface (SU) part of the e n v gene glycoprotein product, and, if present, its structure has little homology with other known ALV SU structures. EAV differ from ALV also in other characteristics of their genome, especially in the LTR arrangement and the composition of terminal nucleotides directing provirus integration. These features might, in a unique way, influence the EAV mode of expression and interaction with the host cell. In the meantime, Payne et al. (1991, 1992) isolated a new ALV from excessively meat-bred chickens, which according to its transmissibility and subgroup specificity did not match any other ALV subgroup and therefore was assigned to a new subgroup (ALV-J). While assessing the structural features of an ALV-J isolate (HPRS-103), Bai et al. (1995) discovered that it is equipped with the e n v gene of EAV origin. EAV genome structures were later

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characterized by sequencing additional EAV clones (Sacco et al., 2000). In addition to the e n v gene, ALV can also acquire an LTR from EAV (Lupiani et al., 2000). In addition, Sacco et aI. (2000) recognized, in newly isolated EAV clones, the presence of avian retroelement ACT sequences (Gudkov et al., 1992; Nikiforov and Gudkov, 1994), i.e., sequences comprising a part of EAV LTR and a stretch of downstream sequences. Therefore, not only recombination between ALV and EAV, but additional recombinational events like those with the ACT retroelement can contribute to the emergence of new viral strains. What impact such an additional genome reshaping has on its pathogenicity is presently unknown. For the well-characterized HPRS-103 virus strain, acquisition of the EAV e n v gene by ALV is sufficient for producing a pronounced alteration in the host range and pathogenicity. Such a recombinant virus spawns efficiently in some economically important chicken strains, and its spread is facilitated by immunological tolerance established by the EAV Env glycoprotein as a consequence of its endogenous expression during embryogenesis. There is full agreement that ALV-J undergoes a high frequency of mutations, which should contribute to its evolution, including development of pathogenicity (Venugopal et al., 1998; Silva et al., 2000). The pathogenic activity has been defined in more detail for the HPRS103 isolate, which preferentially produces myeloid leukosis (myelocytomatosis) targeted to different organs, as well as renal carcinomas (Payne, 1998; Venugopal, 1999). The involvement of oncogene m y c acquisition in its tumorigenic activity is discussed in Section III.

V. ONTOGENY-DEPENDENT RETROVIRUS PATHOGENICITY Since the beginning of retrovirus research, investigators have found that the most successful virus transmission was accomplished using newborn or juvenile animals. Without this procedure, we would be ignorant of a series of oncogenic viruses. Newborn animals differ specifically from adults in several mutually interrelated ways. Among the most important is their lack or low degree of immune response to introduced viral antigen, establishment of immunological tolerance, and developmental immaturity, implying underrepresentation of differentiated versus undifferentiated cells. In analyzing these issues, the avian model is greatly preferable because intravenous inoculation of newly hatched animals, as well as of embryos, is relatively easy. It is, therefore, not surprising that the induction of immunological tolerance was proved in the case of ALV injected in chicken embryos, but not after hatching (Rubin, 1962). This was verified later using more rigid criteria, such as

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the absence of immunochemicallytested anti-ALV antibodies and antibodyantigen complexes in tolerant chickens (Qualtiere and Meyers, 1979). Under natural conditions, avian lymphomatosis induced by RAV-1 (subgroup A) is transmissible only to young chickens, and ALV studies using additional virus strains were performed using either newly hatched or juvenile chickens. A good example of how individual maturity determines the pathogenic consequences of retrovirus infection is offered by chicken osteopetrosis, characterized by bone cell hyperplasia resulting in bone thickening found after inoculation of several ALV strains (Smith, 1982). However, some strains, especially helper virus MAV-2(0) isolated from avian myeloblastosis virus (AMV), were shown to be highly pathogenic (Perbal, 1995). Fortunately, the course of MAV-2(0) pathogenic activity has been studied in relation to the age of inoculated chicken embryos (Hirota et al., 1980; Smith and Ivanyi, 1980). Embryos inoculated intravenously in midembryogenesis produced most profound bone hyperplasia about 3 weeks posthatching. With increased time of inoculation the embryos displayed decreased sensitivity to virus injection. In addition to osteopetrosis, MAV-2(0) intraembryonic inoculation also caused prominent symptoms of wasting disease in chickens, accompanied by bursal and thymic hypoplasia and a decrease in weight. Furthermore, it has been noted that bursal tissue was almost arrested in its development. Interestingly, symptoms of osteopetrosis could have been avoided by the inoculation of syngeneic spleen cells. However, removal of the bursal tissue in embryogenesis did not alter the course of osteopetrosis, suggesting that it was not contributing to this disease (Price and Smith, 1981). Because no more specific cell therapy experiments have been performed, the critical cell target(s) hit by the virus and responsible for the disease was not identified. The most probable candidates, osteoblasts, were found in in vitro experiments to be as sensitive to virus infection as fibroblasts. However, in the diseased bone, an increase in viral DNA and the gag gene product was noticed. The presence of some modifying factors, including intermediates of osteoblast differentiation, in the bone tissue but not in cultured chondroblasts, which should be more sensitive to alteration by the virus, has been invoked (Foster et al., 1994). According to our observation, ALV-C and ALV-D injected intravenously in chicken embryos and ALV-C in duck embryos (Trejbalovfi et al., 1999) also cause pronounced signs of wasting disease, together with a prominent loss of body weight and decreased thymus and bursa mass, with clear cortical cell depletion in both lymphoid organs. Altogether, these data suggest that different lineages of lymphoid cells might be perturbed during embryogenesis by some ALV strains, directly or indirectly and to various degrees. Osteopetrosis virus MAV-2(0) (Paterson and Smith, 1978; Cummins and Smith, 1988), as well as ALV subgroup B and D (Smith and Schmidt, 1982),

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when injected on the 8th to 10th day after hatching, and ALV subgroup C applied during embryogenesis (Karakoz et al., 1980) induce profound anemia. In the experiments where 8- to 10-day-old chickens were infected, both erythropoietic and granulopoietic cell depletion in bone marrow, but no changes in lymphoid organs, were noted. This agrees with our recent observation that lymphoid organ deterioration occurs only after intraembryonic injection. Anemia was manifested by a progressive loss of erythrocytes, their increased osmotic fragility, severe pancytopenia, and misdirected iron incorporation not in erythrocytes, but predominantly in the liver. The latter observation supports the interpretation that hematopoietic tissue integrity (micromilieu) had been damaged. The involvement of the Env glycoprotein in anemia induction has been further stressed by MAV-2(0) genome reconstruction, which defined the env(TM)-LTR region to be of decisive importance (Aurigemma et al., 1991). In addition, a direct toxic effect on bone marrow precursor cells should be considered, especially as it was demonstrated that in the case of a Fr-MLV variant (clone FB29), the Env protein synthesized from the expressed env gene-containing construct is directly toxic for a certain subset of bone marrow cells both in vivo and in vitro (Mazgareanu et al., 1998). Hematopoietic progenitor cell disorders, especially the suppression of myeloid and erythroid lineages, were found to be associated with other retroviral infections, including SIV (Watanabe et al., 1990; Mandell et al., 1995) and HW (Spivak et al., 1984; Schneider and Picker, 1985; Treacy et al., 1987; Folks et al., 1988; Steinberg et al., 1991; Zauli et al., 1994, 1996). Other work (Zauli et al., 1996) suggests that HIV Env glycoprotein (gp 120) interaction with cell receptors is responsible for this suppressive effect. An indirect HW influence on hematopoiesis in the absence of virus infection of stem cells was also proposed (Marandin et al., 1996). Avian REV viruses were also shown to produce the runting syndrome characterized by thymus reduction, anemia, and immunosuppression when injected into neonatal chickens (Mussman and Twiehaus, 1971; Witter, 1984). The involvement of viral genome regions in producing REV pathogenicity was evaluated by Filardo et al. (1994), who, on the basis of a recombinant study, concluded that cooperative gag and env action is of primary importance. An orphan disease produced especially after intravascular ASV inoculation in embryos or in chickens soon after hatching has been described (Duran-Reynals, 1940; Milford and Duran-Reynals, 1943) and proposed to be caused by the destructive virus activity on endothelial cells followed by capillary rupture. An additional histological study led to the proposition that endothelial and myeloid cell hyperplasia was involved in the formation of hemorrhagic cysts (Coates et al., 1968) and that a correlation exists between angiosarcoma occurrence and cyst formation (Aurigemma et al.,

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1991). These aforementioned interpretations were not reconciled, but the disease was also encountered in rats inoculated neonatally with different RSV strains (Svet-Moldavsky, 1957; Zilber and Kryukova, 1957; Svoboda and Grozdanovi~, 1960). There may also be a third way to induce hemorrhages. Subsequent to the production of neurologic disease after intracerebral inoculation of newborn mice with a virus related to Fr-MLV (TR1.3), syncytia formation was found by the discovery of the fusion of endothelial cells in cerebral vessels. Their primary role in intracerebral hemorrhages, thrombosis, and overt central nervous system disease was evoked (Park et al., 1993, 1994a,b). A critical single amino acid mutation that led to this neuropathogenicity was located in the SU env gene region. Further characterization of TR1.3 virus strain pathogenicity confirmed that this virus mutant induces syncytia formation in cells that display a lower density of virus receptors, but an additional as yet undefined cell factor(s) may also determine virus fusogenic activity (Chung et al., 1999). Similarly, brain endothelial cell tropism has been recorded in other neuropathogenic Fr-MLV (PVC-211), however, in the absence of hemorrhages. Its pathogenicity was again assigned to the SU part of the env gene (Hoffman et al., 1992; Masuda et al., 1992, 1996). In fact, in the avian model, a hemangioma-inducing virus has been described, the e n v SU glycoprotein of which produced cytopathogenic effects in a wide range of target cells, including endothelial cells, but its subgroup specificity has not yet been defined (Resnick-Roguel et al., 1989). The fusogenic activity of retroviruses was originally recognized by Klement et al. (1969) as a by-product of repeated and ultimately unsuccessful tests of the ability of MLV strains to complement the unexpressed RSV genome in mammalian virogenic cells (Svoboda, 1960; Svoboda et al., 1963). Because multinuclear syncytia are not viable, it became apparent that fusogenic retrovirus action can produce pathogenic consequences; this is also true for SIV and HIV. There is a good evidence for the involvement of the TM portion of the Env glycoprotein when HIV is injected into cells through the cell membrane in increasing HIV pathogenicity and fusion activity, depending on changes in the Env glycoprotein (Binley and More, 1997; Doms, 2000). These data and additional observations (Stocker et al., 2000) suggest the possibility that a certain composition of the SU Env domain in interacting with cognate receptors on CD4 + T cells might trigger the initial steps in cell membrane perturbation. These steps, even in the absence of visible syncytia formation, are cytotoxic enough to produce a lethal effect. Additionally, this effect may be amplified by the contact of virus-producing cells with their uninfected neighbors. The experience of monitoring retrovirus activity in both neonatal and adult animals gained from the past studies has been implied to SIV, particularly in relation to the development of safe vaccines. From initial studies

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it became apparent that SIV injected into amniotic fluid is pathogenic (Fazely et al., 1993) and that it produces fulminant AIDS-like symptoms in juvenile rhesus monkeys (Bohm et al., 1993; Baba et al., 1994). A promising SIV-attenuated live vaccine deleted in accessory genes nef and vpx and in the negative regulatory element (NRE) protected adult animals, but was pathogenic when injected into neonatal animals (Baba et al., 1995; Ruprecht et al., 1996a). Symptoms of AIDS were noted in a portion of orally infected neonatal animals (Wyand et al., 1997) and in all neonatal animals infected orally or intravenously (Baba etal., 1999). Despite the fact that high amounts of virus (about two Jogs more than used for adult macaques) were employed, these experiments provide a warning against residual pathogenicity of the tested vaccine. Indeed, using a new virus construct with a large nef deletion, Sawai et al. (2000) have proved pathogenicity of such a virus even for adult macaques, associated with partial reconstruction of a functional but truncated nef version. This underscores the fact that a single retrovirus gene mutation, notwithstanding its importance, is not sufficient for virus attenuation. The reason for the high sensitivity of neonatal monkeys has not been established and lies within the scope of speculations about similar findings with other retroviruses (see earlier discussion). Not surprisingly, some SIV nonpathogenic strains, such as SIVmaclAll, do not produce any harm to juvenile macaques (Marthas et al., 1995). Similarly, introduction of SIVagm, indigenous and nonpathogenic for green monkeys, into newborns did not produce any signs of augmented viral load or pathogenicity, despite increased numbers of CD4 + T target lymphocytes in neonatal animals (Beer et al., 1998). Thus, the main issue for safe vaccine design requires removal of those parts of the viral genome required for pathogenicity, as well as tests confirming the lack of pathogenicity in immature hosts. Generally, an infection of neonates makes it possible to detect initially unrecognized retrovirus pathogenicity because of both high representation of undifferentiated cells and marginal immune response, allowing virus replication to reach a critical level at which its pathogenicity is manifested. This also holds true for viral mutants stripped of gene sequences that contribute significantly to virus replication.

VI. SUBVERSION OF IMMUNITY The ability of both mammalian and avian retroviruses to induce immunodeficiency in infected hosts was recognized far before AIDS and studies of primate retroviruses such as HIV and SIV. Avian retroviruses may provide an example of how this topic has been tackled and defined. Early observations suggested a slightly decreased antibody response (Peterson et al., 1966;

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Dent et al., 1968; Purchase et al., 1968) and impairment of phytohemagglutinin (PHA)-induced leukocytoblastomogenesis (Granlund and Loan, 1974; Meyers et al., 1976) in chickens infected with ALV. However, the viruses employed represented mainly field strains of ALV that had not been defined according to their env gene properties (subgroup specificity), which plays an important role in virus pathogenesis. Based on a broader comparison scale, Rup et aI. (1982) established that ALV subgroup B, in contrast to subgroup A, induces suppression of a splenic cell blastomogenic response to PHA. This was in accordance with a previous observation that MAV-2(0), also belonging to subgroup B and responsible for rapidly progressive osteopetrosis, also produces suppression of PHA-induced T-cell blastomogenesis and formation of hemolytic plaques by spleen cells (Smith and van Eldik, 1978). The impairment of blastomogenesis could have been complemented by the addition of noninfected macrophage cells, which indicated clearly that dysfunction of these accessory cells played a major role in blastomogenesis suppression (Price and Smith, 1982; Cummins and Smith, 1987). This probably also resulted in a reduced clearance of bacterial infection (Cummins et al., 1988). Contrary to ALV, inoculation of avian REVs triggers a rapid appearance of a suppressor spleen cell population, which impairs the PHA-induced blastomogenic response even when added to normal PHA-exposed peripheral blood lymphocytes (PBL) or spleen cells. This active suppression mediated by suppressor cells requires the cell-to-cell contact between suppressor and target cells (Carpenter et al., 1977,1978a,b; Scofield and Bose, 1978; Rup et al., 1979). The nature of the suppressor cells is unknown, but their immunosuppression requires the presence of larger amounts of the replicating virus, which favors the possibility that some viral proteins, especially Env glycoprotein expressed at the surface of certain lymphocytes, might be involved and cause a toxic or immunosuppressive effect. However, a series of observations made over the years according to this line of investigation and focused on the retrovirus immunopathogenicityhave been further elaborated more recently (Haraguchi et al., 1997; Denner, 2000). They support the view that the Env glycoprotein, especially its conserved part in the TM region, is involved in immune response dysregulation and immunodeficiency. Exhaustive reviews covering the field of murine leukemia viruses (Moloney, 1964; Rich and Siegler, 1967; Gross, 1970) and their ability to produce immunodeficiency have been already provided (Klein, 1966; Notkin et al., 1970; Dent, 1972; Bendinelli et al., 1985). From experience with both avian and mammalian retrovirus, more general conclusions can be drawn. 1. Retrovirus strains differ in their immunopathogenicity, which is specified by properties of their gene products, mainly by Env glycoproteins. Furthermore, retrovirus infection is influenced deeply by the genetic makeup of the host, as was documented clearly in the case of Fr-MLV in mice, where

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both major histocompatibility (MHC) and non-MHC genes determine the outcome (Chesebro and Wehrly, 1979; Hasenkrug and Chesebro, 1997). 2. In certain cases, virions themselves or virus-producing cells can downregulate the immune response. 3. Despite provoking both B- and T-cell-mediated immunity, retroviruses primarily impair the function of accessory cells such as macrophages, which lose the capacity to produce the required stimulatory molecules. To understand retrovirus pathogenicity, we should know which cells become virus targets in the course of infection. These questions were tackled in previous investigations, which pointed to the important role of the macrophage lineage. This has also been verified more recently using the virus from AKR mice producing thymic lymphomas, which arose by a set of recombination events (see Section IV) among three different types of endogenous retroviruses. Further analysis of this virus yielded good evidence for the primary involvement of dendritic cells (DC) in the infection process. Because the description of DC is a relatively new achievement in immunology, we describe their essential features (Banchereau and Steinman, 1998; Th~ry and Amigorena, 2001). As suggested by their name, dendritic cells display fine dendritic processes, which allow them to interact with other self or nonself cells. The designation of DC includes DC that arose from bone marrow stem cells or from blood monocytes capable of ingesting antigens with several orders of magnitude higher efficiency than macrophages and which efficiently stimulate the expansion of both CD8 + cytotoxic and CD4 + helper cells. Follicular dendritic cells (FDC) are of unknown origin and ensure the differentiation and growth of B cells. Thus, there appears a new paradigm according to which DC represent an early gateway for retrovirus entry (Hays et aI., 1990; Kim et al., 1991; Uittenbogaart et al., 1998). More recently, an involvement of bone marrow-derived, antigen-presenting DC in retrovirus immunodeficiency became apparent (Gabrilovich et al., 1993, 1994a,b, 1996). This was heralded by previous ultrastructural studies (Hanna et al., 1970) and the observation that DC are able to complement an inherent defect in the cytotoxic T lymphocyte reaction against Mo-MLV (Kast et al., 1988). Dendritic cells from Rauscher leukemia virus (Ra-MLV)- infected mice are suppressed in their capacity to stimulate the T-cell proliferative response in mixed leukocyte reaction and to cluster with T cells, which is linked with the downregulation of MHC class II and adhesion receptor LFA-1, including failure of migration and reduced activation by mitogen (concanavalin A). The important finding that IL-12 added exogenously to impaired DC restores their normal activity to a high degree and prevents the symptoms of immunodeficiency supports the notion that DC are not completely depleted, but are stripped of certain functions required for the establishment of a

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complex immune reaction (Williams et al., 1998; Kelleher et al., 1999). The switch of IL-12 to IL-4 production could have shifted T-cell differentiation in the direction to Th2 cells, which act as T-helper cells, preferentially stimulating an antibody response at the cost of a protective cytotoxic response (Kelleher et al., 1999). Thus, the functional changes in DC and in FDC present in the follicles of secondary lymphoid tissue, such as spleen and lymph nodes, became a meeting point among murine leukemia and primate (SIV, HIV) retroviruses and have been identified as important virus reservoirs (Knight and Patterson, 1997; Banchereau and Steinman, 1998). These cells contribute to virus spread. Despite initial hyperplasia, their renewal is impaired, and in advanced stages of disease, they undergo involution (Tenner-Racz and Racz, 1995; Burton et al., 1997). Preferential activation of Th2 cells by changes in the cytokine spectrum is also generally encountered in HIV infection (Knight and Patterson, 1994; Clerici et al., 1997). More recent development indicates clearly that the degree of DC maturity controls the immune reaction via T regulatory cells (Tr), producing certain cytokines and cell surface markers, which determine Thl versus Th2 activation. Apparently, the encounter of immature DC with Tr favor establishment of immunological tolerance (Roncarolo et al., 2001). Furthermore, Tr expansion responsible for nonspecific immunosuppression in persistently FrMLV-infected mice has been documented (Iwashiro et al., 2001). Although not fully understood, multifaceted interactions of DC-T lymphocytes are likely to have a significant impact on the outcome of immune reactivity. Because retroviruses interact efficiently with both these cell types, they can modulate their interaction to an extent that results in immune response deregulation.

Vll. H E T E R O T R A N S M I S S I O N OF RETROVIRUSES Transmission of retroviruses from the species of their origin to foreign species (heterotransmission) was already attempted by Peyton Rous, who, however, succeeded in replicating RSV only on the chorioallantoic membrane of duck embryos, but not in adult ducks (Murphy and Rous, 1912). The first successful RSV passage through Khaki Campbell ducklings was accomplished by Purdy (1932). This model was then followed in detail by Duran-Reynals (1942), who established that the ducks are sensitive to RSV inoculation only 24 hr after hatching. Either immediate or late-appearing tumors--after several months--were observed. Both late and passaged tumours in ducklings acquired an increased affinity to the duck host at the expense of virus transmissibility to chickens. Similarly, the "duck-adapted" RSV was also transferred to more phylogenetically unrelated species, in this

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case to pigeons (Borges and Duran-Reynals, 1952; Duran-Reynals, 1946). Among the memorabilia of retrovirology is his statement: " . . . t h e great variety of tumours and still other facts described emphasize the instability and the great capacity for variation of the viruses inducing the tumours . . . . " This far-seeing topical statement regarding the inherent propensity of retroviruses to undergo genetic changes and to become adapted to a new host could be used as a heading for any review of retrovirology, despite the fact that it was given in the early 1940s (Duran-Reynals, 1942). One of the first encounters of one of us (J.S.) with RSV was the effect of the sensitivity of ducklings to this virus by inducing immunological tolerance to chicken tissue antigens. In a series of papers summarized in Svoboda (1961), it became apparent that intraembryonic or postnatal application of chicken blood increased the time interval during which RSV retained its oncogenicity in foreign duck species. It was hard to interpret these findings, but I had enough courage to propose that RSV might have provided information leading to the appearance of certain chicken antigens, analogous to lysogenic conversion in some phage-infected bacteria. Quite independently, Shoyab et al. (1975) found that B77 ASV, when passaged repeatedly in duck cells, acquired up to 6% RNA of duck origin, which were lost after virus passages in chicken cells. There remains some indistinct but uncertain possibility that retroviruses under certain circumstances have the ability to acquire normal, nononcogenic host cell information, which could modify the cell antigenic makeup. On the occasion of my visit to the United States, I asked several American colleagues about Duran-Reynals and his work. I was getting different answers, but his results were essentially regarded as an oddity. Looking at the present scene of retrovirology, it is clear that Duran-Reynals' findings and far-seeing ideas enlightened this field and were completely validated later on. Many years later, Harry Rubin (1965) made a great leap forward. He discovered that sensitivity to avian retrovirus infection is governed by cellular dominant genes, which, as we know now, code for receptors utilized by retroviruses for their entry into the cell (Weiss and Taylor, 1995; Sommerfelt, 1999; Schneider-Schaulies, 2000). More detailed elaboration led to classification of ALSV subgroups (A to J) on the basis of their ability to infect avian cells of different genetic background and species origin (Payne et al., 1992). Duck cells were identified as sensitive only to subgroup C. Unfortunately, we do not know the subgroup specificity of Duran-Reynals' duck-adapted virus, but his findings were confirmed by Zarling and Temin (1976), who, using ASV subgroup C, isolated a duck-adapted variant capable of replicating in duck fibroblasts. This was achieved by a two-step virus selection on duck cells and only in part of individual viral progeny that were tested. According to our experience (Hlo~finek et al., 1979), when PR RSV-C was employed, the duck-adapted phenotype appeared gradually after an

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initial dramatic drop of RSV infectivity. The duck-adapted variant was also cloned molecularly and the sequence of its env gene showed that it differed from the original virus in 15 amino acid residues and in the loss of 2 out of 14 potential glycosylation sites (Zubak et al., 1989). The full sequence of this virus revealed two changes in LTR enhancers, as well as 18, 5, and 7 amino acid substitutions in gag, pol, and v-src, respectively (Kashuba et al., 1993). We are still lacking the answer to the nature of events leading to adaptation. It should be stressed that adaptation relates to RSV replication because nonadapted virus efficiently transforms duck cells, but almost no virus progeny is synthesized. This block is in some way dependent on the oncogene v-src presence in the virus because transformation-deficient mutants lacking v-src do replicate in duck cells to the same extent as in chicken cells (Shimakage et al., 1979; Geryk et al., 1980). Thus, duck RSV adaptation represents the first repeatedly tackled model to elucidate retrovirus variation in heterologous cells, which should eventually be clarified. Further investigation of ALSV heterotransmission provided strong evidence that either by recombination or by virus selection in mixed cultures of sensitive and resistant cells, dual-tropic variants can arise that infect both types of cells. Thus, an extended host range can be achieved, allowing successful infection of some foreign species cells (Tsichlis et al., 1980; Dorner et al., 1985). Surprisingly, sequence analysis of a dual- tropic variant revealed only two amino acid substitutions within the SU portion of the Env glycoprotein, suggesting that an extended host range can be achieved by very few amino acid mutations (Taplitz and Coffin, 1997). Great progress was achieved by the cloning of ALV cell receptors termed tumor virus (tv) loci, first defined genetically as autosomal genes. The cloning was successful with tv-a and tv-b, allowing ALV cell entry for subgroups A and B, D, E, respectively. A nucleotide homology search revealed that tv-a is related to the ligand-binding domain of the low-density lipoprotein receptor (LDLR) (Bates et al., 1993, 1998; Young et al., 1993). In contrast, the tv-b receptor complex belongs to the tumor necrosis factor receptor family (TNFR) (Brojatsch et al., 1996; Smith et al., 1998). It is interesting that the B and D subgroups are cytotoxic to cells (Dorner and Coffin, 1986), which might be related to TNFR usage for virus entry. That this is the case has been substantiated by further experiments implicating apoptosis involvement. Interestingly, subgroup E derived from the nonpathogenic endogenous retrovirus (RAV-0) can also acquire the cytopathic activity provided that certain cellular protective factors are blocked (not yet fully defined) (Brojatsch et al., 2000). We should note that tv-b is a heterogenous entity, because in addition to molecular clones that facilitate infection with B, D, and E viruses after being transfected to cells lacking tv-b (Adkins et al., 2000), clones coding

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for a receptor interacting with only one or two members of these three subgroups have been isolated (Brojatsch et al., 1996; Snitkowsky and Young, 1998; Adkins et al., 2000). Furthermore, the situation is also more complicated in the case of the tv-a receptor. Using a proper selection procedure, ALV(A) mutants changed in three amino acids were identified, which bound normally to the chicken tv-a receptor, but with low affinity to the same receptor of Japanese quail origin (Holmen and Federspiel, 2000; Holmen et al., 2001). These data point to the conclusion that even within the same type of viral receptor, there are significant species-specific structural and functional differences. It is therefore not surprising that infection of a foreign species host with the same virus can lead to different outcomes. According to our current model for early steps of infection, the receptor activates the Env glycoprotein, triggering conformational changes (Chan and Kim, 1998; Dimitrov, 2000). This subsequently leads to the fusion of the viral envelope with the cell membrane (Einfeld and Hunter, 1988; Hernandez et al., 1997). The fusion step depends on the number of Env molecules, as well as on the density of cell receptors (Gilbert et al., 1995; Damico et al., 1998; Damico and Bates, 2000). Therefore, both of these factors should also play important roles in particular virus pathogenicity, reflecting the extent of the cell membrane damage. Chimeric ALV that acquired the e n v gene from MLV yielded a new efficient experimental setting. For ALV chimera construction, amphotropic MLV e n v (functionally corresponding to that of dual-tropic MLV, but employing another cell receptor; see Section III) was inserted into ALV, making entry into avian cells possible. The virus obtained did not replicate efficiently, but after multiple passages in chicken embryos, a high replication virus emerged, which displayed one amino acid change in env. From this mutant that produced cytopathic changes, a nonpathogenic virus strain arose again by passaging and selection. It was demonstrated that a second mutation in e n v was responsible for a noncytopathic phenotype (Barsov and Hughes, 1996; Barsov et al., 2001). This in fact clearly illustrates the major consequences of a single genetic change in the env gene for the outcome of cell infection. From the point of view of heterotransmission, avian retroviruses belonging to the group mentioned in Section II and called reticuloendotheliosis viruses (REV) are of special significance. This group includes REV-T isolated from turkeys, duck infectious anemia virus (DIAV) and spleen necrosis virus (SNV)--both of duck origin--and finally chicken syncytial virus (CSV). Early studies indicated clearly that this group of viruses is unrelated to ALV, but resembles mammalian type C viruses. This was supported by viral antigenicity and genome structural studies (Theilan et al., 1966; Maldonado and Bose, 1971; Kang and Temin, 1973; Mizutano and Temin, 1973; Purchase

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et al., 1973; Barbacid et al., 1979). In REV isolated from turkeys (REV-T), a new oncogene v-rel was recognized belonging to the Rel family of transcription factors similar to independently defined activator protein NF-KB (Thanos and Maniatis, 1995; May and Ghosh, 1998). The oncogene v-rel is a chimera consisting of c-rel and env gene sequences. Additional mutations and truncation are required for its efficient transformation effect for both birds and mammals (Gilmore, 1999). More specifically, the oncogene activity of replication-defective REV-T attracted attention, and it has been established that when it is complemented by CSV infection in newly hatched chickens, it produces B-cell tumors containing mature IgM-positive B cells. In contrast, when defective REV-T is complemented by a REV helper virus (REV-A), lgM-negative tumors of myeloid or T-lymphoid origin arise (Barth and Humphries, 1988a,b; Barth et al., 1990). These findings indicate an important role for the helper virus in modulating REV-T oncogenicity. An influence of B-cell maturity on REV-T transformation has also been established. Transformed embryonic spleen lymphocytes lack the heavy chain Ig rearrangement in contrast to spleen cells from 1-week embryos exhibiting such Ig rearrangement and usually secreting IgM and, in some instances, also IgG (Zhang et al., 1989). However, using conditional v-rel mutants, it was shown that v-rel switch-off in transformed bone marrow leads to DC and neutrophil differentiation, indicating either direct or indirect involvement of v-rel in several types of hematologic progenitor cells (Boehmelt et al., 1995). REV-T can be transmitted to a wide range of species, such as chickens, quails, ducklings, goslings, and pheasants, which illustrates its broad host range (Theilen et al., 1966; Olson, 1967; Taylor and Olson, 1972). Detailed phylogenetic comparison among various retroviruses and their hosts confirmed that REV retroviruses are highly homologous in their LTR region and that they most likely arose by interclass heterotransmission of mammalian retroviruses, which, according to the structural similarity among REVs, should have occurred relatively recently (Martin et al., 1999). How such a rare event might have happened is at present more than just a matter of speculation. Thus, it was demonstrated clearly that REV sequences, especially LTRs, have been integrated in avian herpesviruses and that they can modify herpesvirus functions (Isfort et al., 1992; Jones et al., 1993, 1996). More importantly, the presence of the infectious REV genome in the herpesvirus of turkey (HVT) and in a vaccine strain of fowlpox virus (FPV) was proved by transfection experiments (Isfort et al., 1994; Hertig et al., 1997). Thus, both large DNA viruses can ensure horizontal REV transmission through either a highly stable herpesvirus or possibly by biting insects transmitting FPV. An immediate mammalian ancestor of REV has not yet been identified, but sequence and functional REV genome analysis indicated env homology with simian type D retroviruses and gag-pol homology with

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co-evolution with species B ........... f-

o

I;

ISpeciA~es Fig. 9 Schematic view of retrovirus heterotransmission and coevolution in a foreign species host. Examples are given in the text.

the baboon endogenous virus (BAEV) (Kewalrami et al., 1992). All of these viruses also employ a common cell receptor for virus entry (Tailor et al., 1999; Rasko et al., 1999). However, a mammalian REV ancestor remains to be identified. Horizontal transmission followed by coevolution within a new species (see Fig. 9) has been proposed and substantiated also in the case of endogenous ALV producing infectious RAV-0 progeny. Sequences of this virus were detected only in chickens and their immediate phylogenetic ancestor, Re Junglefowl. Moreover, they are also present in two species of pheasants not closely related to chickens, indicating independent RAV-0 horizontal transfer (Frisby et al., 1979). Several examples of multiple interspecies transfers based on endogenous gag sequence studies, followed again by coevolution with the new host, have been documented (Dimcheff et al., 2000, 2001). Interestingly, horizontal transmission of mammalian C type retroviruses within the mammalian class was first established in the case of BAEV and was also detected in some cat species (Benveniste and Todaro, 1974). An additional important observation was made indicating that the reading flame of endogenous gag sequences has been conserved, despite the millions of years of coevolution with their host. It is hard to interpret this finding, but an altered endogenous gag-like (originally called Fvl) restriction has been found to act as a block to nuclear import of the preintegration complex (Coffin, 1996; Goff, 1996). The same restriction has been proposed to prevent trans-species retrovirus transfers in mammals (Towers et al., 2000). However, whether there is an

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analogous situation in birds is not known at present. Experimental transmission and transformation of mammalian cells with chicken RSV (especially subgroups D and C) have been successfully achieved and further analyzed (Kisselev et al., 1992; Svoboda, 1998). Despite the presence of full proviral copies in mammalian cells, such nonpermissive but virogenic cells regularly fail to produce infectious virus progeny because of blocks in provirus expression, e.g., anomalous splicing, inefficient export of unspliced RNA from the nucleus, posttranslational modification, and virus assembly. However, the virus can be rescued by the fusion of virogenic mammalian cells with permissive chicken fibroblasts, which provide the missing cell function required for virus expression. There has been an ongoing quest to facilitate HIV studies by its heterotransmission to genetically modified mouse cells having the human HIV receptor and coreceptor and, in addition, a cofactor needed for HIV transcription (Garber et al., 1998). These attempts were facing similar blocks in virus expression, which had been pinpointed previously in the case of virogenic RSV-infected mammalian cells (Svoboda, 1998), but most striking was the inefficient assembly and egress of virus particles. However, efficient virus production has been achieved in heterokaryons formed by the fusion of HIV-infected cells with human cells (Bieniasz and Cullen, 2000; Mariani et al., 2001). Nevertheless, other rodent species, especially rabbits (Kulaga et al., 1988; Cho et al., 1995; Dunn et al., 1995) and rats, seem more permissive to HIV infection, but surprisingly this holds true especially for stable cell lines. It was noticed that primary rat macrophage cultures were, in contrast to T lymphocytes, far better suited for virus production (Keppler et al., 2001). Such tissue-specific differences can, on the one hand, skew the pattern of in vivo infection, but on the other hand they may improve the understanding of the role of particular cell types for virus spreading. The mechanism for transcriptional silencing of avian proviruses integrated in a mammalian cell has not yet been elucidated. In the example studied by our group, i.e., integration of the RSV provirus in mammalian cells, provirus methylation is of decisive importance and preventing methylation favors provirus expression (Hejnar et al., 1994,2001). Similarly, methylation down regulates retroviral vector expression not only in heterologous, but also in some differentiated cells (Svoboda et al., 2000). A control over foreign DNA, including proviral DNA, evolved especially in mammals. It is therefore possible that avian cells are more permissive to mammalian retrovirus infection. In addition to the already mentioned REV, there are indications that MLV or murine sarcoma viruses (MSV) pseudotyped with a xenotropic MLV envelope, allowing their entry to duck cells, can undergo detectable virus replication (Levy et al., 1982; Levy, 1978). It should be noted, however, that RSV LTR-driven reporter gene expression is more sensitive to CpG

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methylation, and consequently to transcriptional silencing, in mammalian rather than in avian cells (Hejnar et aI., 1999). Interesting cases of ALSV modification occurred by in vitro passaging through ring-neck pheasant fibroblasts, which yielded recombinants with the pheasant endogenous retrovirus env gene (subgroup F). Such recombinants exhibited new pathogenic activities, e.g., lung lesions corresponding to nonmalignant angiosarcomas, consisting of proliferation of blood vessel endothelial cells (Simon et al., 1984). Serial passaging of mouse Fr-MLV to newborn rats offered a way to isolate a new Fr-MLV variant neuropathogenic for the rat host (Czub et al., 1995; Hein et al., 1995). However, the main interest of retrovirus heterotransmission is focused on the immunodeficiency syndrome. After inoculation of BLV in rabbits, Burny et al. (1985) noticed the occurrence of lethal wasting disease, which they ascribed to immunodeficiency. A well-documented definition of BLV-induced immunodeficiency after the infection of newborn rabbits was then provided, including a negative control represented by BLV stripped of some auxiliary genes and therefore producing a low viral burden (Altanerova et al., 1989; Wyatt et al., 1989; Kucerova et al., 1999). Conspicuous consequences of retrovirus heterotransmission were recognized in Asian macaques, where immunodeficiency and AIDS-like symptoms culminating in stunting lymphoadenopathy, depletion of CD4 + T lymphocytes, and chronic diarrhea accompanied with opportunistic infections were first observed. The retroviruses, collectively called simian immunodeficiency viruses (SIV), reproducing the same disease in macaques were then isolated. Further investigations led to the conclusion that pathogenic SIVs did not originate from macaques, but had been heterotransmitted inadvertently from the sooty mangabey species to macaques because of the absence of strict breeding separation of both monkey species (Desrosiers, 1990; Allan, 1991; Johnson etal., 1991; Hirsch and Johnson, 1993). In this way, the first strains of SIVmac pathogenic hosts in foreign species, i.e., macaques, but replicating harmlessly in sooty mangabeys in the absence of any noticeable pathogenic influence were described. It is noteworthy that the first SIV viral isolates were obtained 2 years after HIV and no attention had been paid to the existence of primate retroviruses before the AIDS pandemics, despite numerous instances of retrovirus modification associated with heterotransmission. The SIV field has been reviewed systematically by Whetter et al. (1999), Hirsch and Lifson (2000), and Overbaugh and Bangham (2001), who provide the full characteristics of individual viral strains and their pathogenicity for various simian hosts. Nevertheless, because of the great importance of primate retroviruses for understanding virus pathogenicity, we would like to characterize in some detail well-defined examples of host-dependent SW immunopathogenicity. As already mentioned, the first SIV isolate was found to be indigenous for

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sooty mangabeys (SIVsm) and the course of infection with this viral strain was subjected to close scrutiny. This led to the conclusion that the virus produces no pathogenic changes in the sooty mangabey monkey species (Fultz et al., 1986, 1990; Marx et al., 1991). Moreover, when sensitive techniques, such as competitive polymerase chain reaction and in situ hybridization, were employed, the amount of SIVsm RNA and the number of proviral copies in lymph node cells in the absence of any damage to lymph node tissue were high and within the range found in SIV-infected macaques (Rey-Cuill8 et al., 1998), where virus infection resulted in AIDS-like symptoms. In contrast, both SIV from sooty mangabeys (SIVsm)and SIV passed in macaques produce immunodeficiency preceded by lymph node hyperplasia in macaques (Ringler et al., 1989; Reimann et al., 1991, 1994; Chakrabarti et al., 1994; Baskin et al., 1995). This is followed by the structural and functional collapse of both lymph node tissue and FDC (Joling et aI., 1992; Rosenberg et aI., 1994). Progression to AIDSqike disease in macaques has been correlated with the degree of viremia (Hirsch et al., 1991; Watson et al., 1997; Ten Haaf, 1998). It was proposed that infected mangabeys with no signs of disease in contrast to macaques may acquire long-lasting CD8 + T-cell inhibitory function (Villinger et al., 1999) or they may exhibit an altered immune response regulation, which does not result in the formation of antigen-antibody complexes damaging the germinal centers in lymph nodes (Rey-Cuill8 et al., 1998). Furthermore, it was suggested that nonpathogenic SIV enhances the apoptotic/cytotoxic effect on CD8 +, but not on CD4 + cells (Dittmer and Hunsmann, 1997). Cytokine balance disturbance influencing the differentiation of T helper cells (Th) might also play a role. For nonpathogenic infection, the switch from Th0 to Thl involved in inflammatory and cell-mediated immunity prevailed, whereas in pathogenic infection, cytokines activating Th2 preferentially stimulating humoral immunity were detected (Benveniste et al., 1996; Dittmer and Hunsmann, 1997); opposite findings were also reported (Villinger et al., 1996). More recent data provide a new complex picture of SIV pathogenesis. Both CD4 + and CD8 + T lymphocytes are augmented, ensuring some balance between cell death and proliferation (Gougeon et al., 1993; Mohri et al., 1998; Rosenzweig et al., 1998). This was also well documented in thymic tissue, a source of immature T lymphocytes, where after the initial wave of apoptosis (soon after infection), progenitor cell proliferation rebounds (Wykrzykowska et al., 1998). However, the final fatal outcome of the disease is accompanied by a fall in CD4 + T cells. What set of events are involved remains unclear. There is no doubt about the cytopathic (apoptogenic) outcome of CD4 + T-cell infection. Furthermore, the virus infection imparts its effect to other cells, noninfected as well, and modulates T-cell expansion and tissue distribution. Infected CD4 + T cells become a target for cytolytic immunity, and their depletion as well as persistent virus replication impinges

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on various facets of the immune response (McClune, 2001), including increased CD4 + T-cell sensitivity to undergo immunological anergy (Bostik et al., 2001). An important feature of the SIVmac infection during its acute stage was characterized by "teethless" CD8 + expansion unable to lyse infected target cells and produce required cytokines (Ogg et al., 1998; Schmitz et al., 1999; Xiong et al., 2001). This is probably caused by insufficient CD4 + helper T cells, resulting in a block of CD8 + T-cell differentiation (McMichael and Rowland-Jones, 2001). Despite data pointing to a crippled function of CD8 -~ T lymphocytes, more recent findings indicate that CD8 + cell depletion leads to a high increase of virus load and to lowering of B and CD4 + T-cell counts (Gallimore et al., 1995; Jin et al., 1999; Schmitz et al., 1999). This suggests that at least some CD8 + cell populations are configured properly for SIV control and provides a rationale for vaccination procedures that enhance their anti-SIV-infected cell activity. However, additional complicating factors, such as a viral mutant escaping the immune response, including a CTL reaction, should be taken into consideration (Evans et al., 1999). In any case, the SIV viral load and SIV ability to replicate and efficiently generate viral variants in the species of its origin (Johnson et al., 1990; Miiller-Trutwin et al., 1996) per se are not sufficient to produce immunodeficiency, and therefore some other factor is likely to be responsible for a peaceful coexistence between SIV and its natural host. However, when comparing the extent of variants of SIVsm in sooty mangabeys with that in the macaque species, where it triggers immunodeficiency, a tendency toward a selection of env changes reminiscent of the highly pathogenic SIV PBj14 strain (see Section III,C) was noted. This indicated the possibility of selection of more pathogenic variants in a heterologous host (Courgnaud et aI., 1998), favored by as yet undefined host factors. The characterization of SIVmacas a virus heterotransmitted from sooty mangabeys to macaques, where it produces AIDS-like disease, made it possible to determine how this virus passaged in heterologous species would act after reintroduction to mangabeys, its natural host. Not surprisingly, SIVmacdid not affect mangabeys and replicated in this host, about three orders of magnitude less efficiently than autochthonous SIV~m, evoking a rapid and long-lasting CTL response (Kaur et al., 1998). In some way, SIVmachas therefore been adapted to the macaque species, losing in part its infectivity for mangabeys, suggesting a parallel to RSV duck adaptation discussed earlier. Several species of green monkeys harboring autochthonous SIVagm,which upon transfer to the macaque species again produce AIDS-like disease, yielded another widely employed experimental setting. This model has also been analyzed using sensitive virus detection procedures. The degree of viremia in green monkeys varies, but can reach values that are found in cases of progression to AIDS (Hartung et al., 1992; Goldstein et aI., 2000).

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The extent of provirus integration in peripheral blood and lymph nodes was lower than provirus integration in diseased macaques (Diop etal., 2000), but other lymphoid tissues, especially the gut, seem to be a major site of virus replication (Broussard et al., 2001); this ensures high levels of viral RNA in the blood. However, no impairment of lymphoid tissues, as represented by lymph nodes and FDC or CD8 + infiltration of germinal centers (Baskin et al., 1995), was detected despite the fact that the virus replicated. SlVagm in its natural host does not damage the immune response. However, some of its manifestations, such as the near absence of anti-Gag and virus neutralization antibodies and the lack of antibody-and complement-dependent cellular toxicity (Norley et al., 1990), as well as decreased virus expression in lymph nodes and FDC (Beer et al., 1996), are distinguishable. Despite harboring the provirus, the number of CD4 + T lymphocytes does not decrease. It was proposed that African green monkey CD8 + T lymphocytes produce an undefined cytokine that can downregulate SIV replication (Ennen et al., 1994). Of some relevance to the nonpathogenic course of infection might be the findings showing a generally high CD8 ÷ and low CD4 + T-cell proportion and the propensity of CD4 + T cells to lose the receptor required for SIV entry (Murayama et al., 1997). Such nonconspicuous changes in the immune response could contribute to avoiding the immunopathogenicity of SIV antigen-antibody complexes and dysfunction of the immune apparatus. The virus glycoprotein is of main importance, as already inferred from early observations (Mann et al., 1987; Shalaby et al., 1987). In accordance with this assumption, it has been documented even more recently that mutations in (tm) and also in SU play a pivotal role in attenuation and probably also in S1V pathogenicity (Luciw et al., 1998; Reitter et al., 1998; Shacklett et al., 2000; Fultz et al., 2001). It should be emphasized that not every heterotransmission results in pathogenic consequences. This is the case of SIVagm, which produces no disease in rhesus macaques but is pathogenic for pig-tailed macaques (Hirsch et al., 1995). Similarly, pathogenic SIVmac evokes only symptomless virus persistence in baboons (Cranage et al., 1992). In the case of macaques, lack of pathogenicity was related to a lower viral load, but this was not found to be the case in baboons. We could imagine that a species of SIV origin evolved resistance to a deleterious outcome of the interaction between SIV Env glycoprotein and virus receptor- and coreceptor-expressing target cells. In a certain way, such a situation would mimic the nonpathogenicity of ALV subgroup A. A mutation between ALV subgroups can be obtained after repeated passages and involves one or a few amino acids. In the course of virus-host coevolution, the least harmful subgroup should be selected positively because it does not threaten host survival. Therefore it is not surprising that ALV-A represents the most common ALV in chicken breeds. An analogous situation was encountered in FeLV, where widely distributed FeLV-A represents the least pathogenic strain (see Overbaugh and Bangham, 2001).

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In SIV, the situation is more complicated by the presence of several accessory genes, which facilitate the SIV life cycle and determine its affinity to lymphoid cells. Some analogous but not homologous functions acting in a speciesspecific way might also be assured in more simple retroviruses such as ALV. This is exemplified by the finding that viral RNA export from the nucleus to the cytoplasm is influenced positively in avian cells by noncoding direct repeats (DR). They seem not to be active in ALV-infected mammalian cells, but nevertheless, this deficiency can be complemented by the lentiviral accessory gene reu and its response element, which fulfil the same transporting function in SIV/HIV virus infection (Sorge et al., 1983; Nasioulas et al., 1995; Ogert et al., 1996). The main significance of high-load SIV nonpathogenicity for indigenous species indicates that the viral load itself is not necessarily followed by immunodeficiency. However, when transmitted to macaques, these viruses become pathogenic and the degree of pathogenicity correlates with the viral load (Hirsch and Lifson, 2000). This is not too surprising because if the heterologous host exhibits a tendency to be damaged in certain functions (especially immunological functions), it would be expected that the virus titer has to reach a certain threshold in order to hit critical numbers of cell targets. The dilemma of SIV nonpathogenicity versus pathogenicity remains unresolved, but it has become obvious that the path to life or death is determined by the species-specific reaction to the infectious virus. This encompasses the extent and degree of the immune reaction, with the selectivity in cytokine mobilization having an impact on the immune response and probably other specificities particularly related to the fine-tuning of the lymphoid organ architecture, lymphoid cell representation, and turnover, and their sensitivity to virus-mediated cell activation and damage. In particular, the strength and the course of the host immune response mediated by CD8 + cells have a significant bearing on the viral load, variation, and pathogenesis (Zinkernagel and Hengartner, 1994; Nowak and Bangham, 1996). At these points, retrovirology merges with cell biology and immunology, and further progress in understanding virus pathogenesis can be expected from a joint venture of both disciplines. However, as discussed in Section Ill,C, some changes in the SIV genome can efficiently modulate virus pathogenicity and if positively selected in foreign species, they should contribute to disease progression. Combining both evolutionary and epidemiological data with structural analysis of SIV isolates from several green monkey species, it became apparent that SIV overcame the species barriers on numerous occasions (Beer et al., 1999). Not surprisingly, host-dependent SIV coevolution with the host species has also been well documented (Allan et al., 1991; Hirsch et al., 1993; Miiller et al., 1993). Dramatic progress has been achieved in understanding the origin of HIV. The comparison of HIV-2 and SIVsmviral isolates using both sequence and

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seroepidemiological approaches led to the conclusion that HIV-2 arose by SIVs~ transmission to humans (Hirsch et al., 1989; Gao et al., 1992, 1994; Sharp et al., 1995; Chen et al., 1996, 1997). As reported more recently, the delineation of SIV strains derived from chimpanzees, especially of three isolates from subspecies troglodytes, may provide a clue to the origin of three HIV-1 groups (Gao et al., 1999). The involvement of other viral isolates from chimpanzees, as well as the possible ways of their spreading to humans and causing immunodeficiency, is discussed in detail by Weiss and Wrangham (1999) and Holmes (2001). These breakthrough discoveries, however, raise new challenging questions. The first concerns the efficiency of virus heterotransmission and changes of the viral genome favoring this event. As recognized so far, not every SIV heterotransfer is associated with efficient spread in the new species, as documented for both HIV-1 and HIV-2. In addition, successful virus expansion seems to be correlated with alterations in the variable (V3) env region (Hahn et al., 2000). As we have learned from ALSV studies, the success of heterotransmission is affected by foreign species host factors and by the site of virus integration in the cell genome. Both can impose different degrees of transcriptional silencing on the provirus or block posttranscriptional modifications. Thus, we need to investigate whether and in which state HIV-related proviral copies are present in humans living in endemic areas. As we have documented with several examples, the process of retrovirus adaptation for foreign species is usually gradual and may require repeated virus transfers selecting the fittest variants. Whether similar stepwise changes also occurred in HIV should be examined further. Finally, there are many SIV isolates (Hahn et al., 2000) that might represent a potential reservoir of new infections and new dangerous recombinant viral strains, and therefore their possible contribution to AIDS pandemics should be monitored in advance of undesirable consequences. Here is a place for a short reflection. For a long period, retroviruses were conceived as an excellent tool for defining oncogenesis. The involvement of these viruses in human disease had not been taken seriously until the discovery of human T-cell leukemia virus (HTLV) and HIV. In fact, there is insufficient evidence to prove that products of human endogenous retroviral genes cause pathogenic consequences. However, the retrovirus threat appeared from without, i.e., from our primate ancestors, reminding us that genetic instability allowing retrovirus adaptation to foreign species represents a real danger. The worst scenario that might happen would be recombination between exogenous animal retroviruses and endogenous human retroviral sequences, the consequences of which are unpredictable. Therefore, any attempts at employing xenografting or live vaccines, even containing only some intact viral gene, should be subjected to full scrutiny, including construction and testing of possible recombinants.

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Understanding of HIV and SIV should widely utilize the knowledge of other retroviruses. An elegant review by Popovi~ and Gr6fov~t (1995) exemplifies how procedures such as cocultivation of rodent cells with RSVinfected chicken fibroblasts led to efficient mammalian cell transformation and how proof of the fusogenic activity of an experimental retrovirus contributed to the first successful HIV transfers to human T-cell lines and to recognition of its pathogenic activity. The wealth of knowledge demonstrating retrovirus induced immunodeficiency in various species also provides a topical argument against any views that HIV per se is not responsible for AIDS.

VIII. SUMMARY AND OUTLOOK Retroviruses have played a pivotal role in the definition of oncogenes as initiators of cell transformation and as important genes contributing to many cases of tumorigenesis. Despite the low probability that new oncogenes will be discovered in retrovirus isolates, the already known viral oncogenes are being employed successfully for the molecular analysis of critical structural and functional alterations that are required and/or contribute to their tumorigenic activity. Because retroviruses not only acquire oncogenes, but can also activate, by their strong promotor-enhancer elements, their normal counterparts called protooncogenes when integrated in their vicinity, further oncogenes should be detected by retroviral insertional activation. According to the growing body of knowledge, constitutively activated oncogenes are needed for maintaining the tumorigenic cell activity and therefore offer a suitable target for therapeutic intervention. The function of oncogenes is closely related to the role of their cognate ancestors--proto-oncogenes--especially involved in cell proliferation, mitogenic cascade, signal transduction, cell behavior, and differentiation. It becomes apparent that the role of the oncogene, as well as of the proto-oncogene, in fundamental cell functions is complex, including a series of molecular cell targets. In addition, proto-oncogenes are tightly regulated in contrast to oncogenes, whose active state is maintained constitutively. Most oncogenes deregulate only some steps leading to cell transformation, and therefore they require either complementation by other oncogenes and additional mutations leading to deregulation of further cell functions, as required for accomplishing full cell transformation. Retroviruses do not play any conspicuous role in the etiology of the vast majority of human tumors. However, they are responsible for the AIDS pandemics representing a threat for certain human populations, particularly in sub-Saharan Africa and Asia. The causative agent HIV has been heterotransmitred from primates to humans, which should remind us that retrovirus

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heterotransmission to humans should be tightly controlled and at best fully avoided. We have to learn what conditions and steps are involved in successful trans-species retrovirus transfer, which has also been documented in avian and mammalian hosts. We are still lacking full understanding of retrovirus-induced immunodeficiency syndromes, AIDS included. Questions that remain to be answered include: why do autochthonous hosts not show signs of immunodeficiency in contrast to foreign species infected with the same virus? what is the exact cause of retrovirus-induced deregulation of the immune system? how does a retrovirus exert its cytopathogenic activity on lymphoid cells? and what is the virus and/or host factors that favor them? We may also learn from other instances of retrovirus-induced immunodeficiency in laboratory animals rather than in primates. Here, in most cases the virus Env glycoprotein is responsible for lymphoid and hematopoieric tissue damage, but unusual virus products, such as the truncated gag gene product in mouse can also play a role, for example, in the murine disease MAIDS, which triggers collapse of the immune system. Comparative retrovirology also provides strong support for the unequivocal etiological role of retroviruses in several immunodeficiency syndromes. So far, critical changes in the primate retrovirus genome structure that are responsible for its immunopathogenicity have not been clearly defined. There are indications that more than one genome region should be modified. This agrees with some observations obtained with other retroviruses, but it is likely that such changes will represent either a certain definable combination of mutants throughout the viral genome or, in some cases, only minor critical alterations in one gene, such as env, might be sufficient. Because at least some of the thoroughly studied retroviruses from different species such as chicken, duck, cat, bovine, or primate produce immunodeficiency under certain conditions, we propose that the attack on the immune apparatus represents an ancestral mechanism allowing retroviral spread. As we are dealing with retroviruses we have to acknowledge that especially after their heterotransmission or integration in germ line or differentiated cells, they are subject to cell regulatory mechanisms. They can therefore be silenced positively but again reactivated. This has an important implication for retrovirus persistence and for the use of retroviruses as vectors for the transmission of genetic information, especially if targeted to differentiated cells. We therefore need to better understand such cell supervision of retroviruses in order to avoid their persistence and to ensure retrovirus vector expression. Despite being the focus of interest, retrovirus immunopathogenicity is not the only pathogenic property of these viruses. Different kinds of neurodegenerative symptoms were revealed in retrovirus infection that seem to be related to the early steps of virus entry in the cell, which is made possible by the fusion of virions with the cell membrane. With the exception of SIVand HIV-induced neurodegeneration, it is not known if and how such a

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Fig. 4. I Possible role of EBV-specific IgA in mediating EBV infection of epithelial cells. EBV-specific IgA is secreted by plasma cells into the subepithelial space and, in the form of polymeric Ig complexes, can bind to the secretory component protein (SC) on the basolateral membranes of epithelial cells. The IgA-SC complex is then endocytosed by epithelial cells and transported to the luminal surface. In case of active EBV replication, such as that presumably occurring in UCNT patients, IgASC complexes could bind EBV virions and transport them into the cytoplasm, thus allowing virus to enter epithelial cells (Sixbey and Yao, 1992). It is noteworthy that the SC protein is expressed on the basolateral membranes of epithelial cells localized in the fossa of Rosemmdler, where UCNT usually develops and localized EBV infection occurs (Nomori et al., 1985).

Fig. 4.2 Possible interactions between UCNT cells and infiltrating T lymphocytes. Phenotypic studies have shown that expressed by UCNT cells and intratumoral T lymphocytes, which presumably allow the occurrence of biologically relevant In particular, the expression of ICAM-1, CD40, CD70, and CD80 is probably induced or enhanced by LMP-1. Increased (Huang, et al., 1999) may favor the intratumoral recruitment of T cells, which, in turn, may provide signals promoting the

immune regulatory receptoriligand pairs are interactions between these cell populations. production of IL-l observed in UCNT cells growth and/or survival of UCNT cells.

Fig. 4.3 Possible role of TGF-B in the pathogenesis of UCNT. The high levels of TGF-B detected in UCNT patients at both systemic (serum) (Xu et al., 1999, 2000b) and intratumoral (Huang et al., 1999) levels may contribute to inhibit NK- and T-cell-mediated antitumor immune responses, thus favoring the escape of tumor cells from immune control, Moreever, TGF-B may cooperate with IL-10 to induce B cells to switch to IgA production (Stavmezer, 1995). Furthermore, TGF-j3 also has the ability to induce the lytic cycle in EBV-infected cells (Di Renzo et al., 1994), thus contributing to the enhanced EBV replication that characterizes UCNT patients. Therefore, TGF-B may not only enhance EBV shedding, but also increase the viral load in the blood and may even favor anti-EBV humoral immune responses within the nasopharyngeal mucosa; this may result in enhanced local production of anti-EBWgA, which, in turn, may mediate further infection of epithelial cells by EBV Small 1 arrows indicate increase ( ) or *crease ( ).

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mechanism is involved in other etiologically undefined human neurodegenerative diseases. It should be kept in mind that the outcome of retrovirus infection is deeply influenced by the maturity of the infected individual. The earlier in ontogeny the virus infects, the more severe and general are the consequences. This also extends to the damage of lymphoid tissues followed by immunodeficiency. Surprisingly, primate retroviruses can produce this condition even when transmitted to proper adult hosts, suggesting that these viruses, being equipped with a series of accessory genes, are either more aggressive or that primate lymphoid tissue retains some features characteristic for neonates. If certain autoimmune diseases have any relation to germ line-integrated (endogenous) retrovirus expression, then we should presume that such expression either bypasses immune recognition and therefore immunological tolerance or that the retroviral genome expression is postponed to the period of immunological maturity. There is no doubt that retroviruses are prone to rapid genetic evolution due to their high mutability and very efficient activity for recombination. This has important consequences for their pathogenicity and ability to adjust their growth to different kinds of differentiated cells and cells of foreign species. As demonstrated in both mice and chicken, recombination of exogenous retroviruses with endogenous retroviral sequences integrated in germ line cells can lead to a dramatic increase of pathogenicity and host range. Thus, not only horizontally transmissible infectious retroviruses, but also retroviral genes residing in our genome can potentially contribute to the genesis of new pathogens. Since the last review in this series devoted to the topic of retrovirus pathogenesis (Enrietto and Wyke, 1983), retroviruses have struck the human population as an AIDS evil (Dalgliesh and Malkovsky, 1988; Gaidano and DallaFavera, 1995). Let this be a warning to all that we have to reveal in detail the pathogenic potentials of retroviruses on a broad comparative scale and to learn as much as possible about their life cycle and refined intercourse with cell functions and cell genes.

ACKNOWLEDGMENTS The authors thank H. Roubalovfi for help with the recovery of original articles; S. Takfi~ov~l for typing and correcting the text; J. Hejnar, I. Hirsch, and J. Plach% and J. A. Wyke for critical comments; and J. Levin and R. Dourmashkin for English style improvements and corrections. One of us (J. S.) wishes to express special gratitude to J. Hejnar for his encouragement and support. We thank George Klein for challenging questions that he raised at several meetings and that inspired us to write this article. We also thank him for his review of January 22, 2002, by which he accepted our article for publication. We apologize to our colleagues that due to limited space

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we omitted a series of important topics and references. Due to a delay in printing, we cover the literature until the end of 2001. Our work was supported by Grants 312/96/K205, 524/01/0866, 204/01/0632, and 204/02/0407 awarded by the Grant Agency of the Czech Republic.

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