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Retrovirus-induced disease in poultry
Retrovirus-Induced Disease in Poultry L. N. PAYNE1 Institute for Animal Health, Compton, Newbury, Berks, RG20 7NN, United Kingdom DNA proviruses (often defective) in host germ cell genome, and are termed endogenous viruses. Several other families of endogenous viruses also exist, one of which, endogenous avian retrovirus (EAV), is related to Subgroup J ALV. Exogenous viruses, and sometimes endogenous viruses, can have detrimental effects on commercially important production traits. Exogenous viruses are currently controlled by virus eradication schemes. Reticuloendotheliosis virus, which lacks a viral oncogene, causes chronic B cell and T-cell lymphomas in chickens, and also chronic lymphomas in turkeys and other species of birds. An acutely transforming variant of REV, Strain T, carries a viral oncogene, and induces reticuloendotheliosis within a few days. In chickens and turkeys, REV spreads vertically and horizontally. No commercial control schemes are operated. In turkeys, LPDV infection has occurred in several countries, where it caused a lymphoproliferative disease of uncertain nature.
(Key words: chicken, oncogenesis, retrovirus, tumors, turkey) 1998 Poultry Science 77:1204–1212
INTRODUCTION It is now some 90 yr since Ellermann and Bang (1908), working in Copenhagen, and Rous (1910), in New York, showed that leukemia (leukosis) and sarcomas in the domestic fowl have a viral etiology. Over the following decades, diseases of the so-called avian leukosis complex became the major cause of mortality in poultry in many countries, which stimulated extensive investigation in many veterinary laboratories in attempts to try to understand and control these conditions. At the same time, many medical workers worked with Rous sarcoma virus (RSV) and the avian leukosis viruses (ALV) as model systems with which to study the role of viruses in the causation of tumors. As a consequence, an enormous body of literature has been accumulated, and probably more is known about the avian leukosis/sarcoma virus
Received for publication August 3, 1997. Accepted for publication February 17, 1998. 1To whom correspondence should be addressed.
(ALSV) group of viruses and the diseases they cause than about any other avian pathogen. We now know that the viruses concerned are retroviruses, that is, RNA viruses that replicate via a DNA proviral stage linearly present in the host genome, by virtue of the presence in the viral genome of a pol gene that encodes the enzyme reverse transcriptase necessary for the transcription of RNA to DNA. The ALSV species of retroviruses are currently classified in a genus termed “ALV-related” in the family Retroviridae (Coffin, 1992). Another species of avian retrovirus, reticuloendotheliosis virus (REV), discovered in turkeys in 1958 (Theilen et al., 1966), is placed in the subgenus Reticuloendotheliosis, of the genus MLV-related [reflecting, unexpectedly, a relation-
Abbreviation Key: AEV = avian erythroblastosis virus; ALSV = avian leukosis/sarcoma virus; AMV = avian myeloblastosis virus; EAV = endogenous avian retrovirus; gs = group-specific; LPDV = lymphoproliferative disease virus; LTR = long terminal repeat; MLV = murine leukemia virus; REV = reticuloendotheliosis virus; RSV = Rous sarcoma virus; SU = gp85 surface.
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ABSTRACT Three species of avian retrovirus cause disease in poultry: the avian leukosis/sarcoma virus (ALSV), reticuloendotheliosis virus (REV), and lymphoproliferative disease virus (LPDV) of turkeys. The ALSV can be classified as slowly transforming viruses, which lack a viral oncogene, and acutely transforming viruses, which possess a viral oncogene. Slowly transforming viruses induce late onset leukoses of the B cell lymphoid, erythroid, and myeloid cell lineages, and other tumors, by viral promoter insertion into the genome of a host cell and activation of a cellular protooncogene. The various acutely transforming leukemia and sarcoma viruses induce leukotic or other tumors rapidly and carry one or another (sometimes two) viral oncogenes, of which some 15 have been identified. The ALSV fall into six envelope subgroups, A through E, and the recently recognized J subgroup, which induces myeloid leukosis. With the exception of Subgroup E viruses, these viruses spread vertically and horizontally as infectious virions, and are termed exogenous viruses. Subgroup E viruses are usually spread genetically as
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ship with murine leukemia virus (MLV)]. Two other species of avian retrovirus, both unrelated to ALV and REV, have also been described: lymphoproliferative disease virus of turkeys (LPDV; Biggs et al., 1978) and the little studied pheasant type C oncoviruses (Hanafusa et al., 1976). These two species have yet to be placed in Coffin’s “new taxonomy”. Many research reviews and text-book accounts of these avian retroviruses exist; recent examples including De Boer (1987), Payne (1992), and Payne and Fadly (1997). The present article will focus particularly on the pathogenesis and control of avian retrovirus-induced disease, with emphasis on areas of current research interest of relevance to the poultry industry.
Avian leukosis/sarcoma viruses induce leukoses affecting the erythroid, lymphoid, and myeloid series of hematopoietic cells, and a number of solid tumors, including those affecting cells of the mesenchyme, kidney, ovary, testis, liver, pancreas, and nervous system (reviewed by Beard, 1980; Purchase, 1987; Payne and Fadly, 1997). Significant progress has been made in understanding the molecular basis for the induction of a number of these conditions. Two types of ALV are recognized, slowly and acutely transforming, and their genetic makeup is known.
Slowly Transforming ALV Slowly transforming ALV are simple retroviruses, possessing the structural genes, gag, encoding the internal structural proteins of the virion; pol, encoding the RNAdependent DNA polymerase (reverse transcriptase); and env, encoding the viral envelope. They are arranged in the order 5′gag-pol-env3′. In the RNA form of the virus, they are flanked by controlling sequences and these form the long terminal repeat (LTR) sequences in the proviral DNA form. These viruses are termed slowly transforming because the tumors they induce are late in onset after infection of the chicken. It is known that these viruses induce lymphoid leukosis and erythroid leukosis (erythroblastosis) by insertional mutagenesis in which ALV genome with its LTR region becomes genetically integrated just upstream, downstream, or within a cellular proto-oncogene of the host. The cellular proto-oncogene becomes activated by the promoter or enhancer sequence of the LTR, leading to abnormal expression of the oncogene and to neoplasia. Differences in LTR sequences and the presence of specific LTR binding proteins are believed to determine the type of cell that is transformed. The commonest neoplasm induced by slowly transforming ALV is lymphoid leukosis. In this disease, the cmyc gene (or also c-myb experimentally) in a bursal lymphoid cell (B cell) is activated (reviewed by Kung and Maihle, 1987; Neiman, 1994). The tumor cell nuclei show
increased amounts of 62 kd Myc phosphoprotein. B Cell lymphomagenesis is a multi-stage event, with activation of other cellular oncogenes leading to tumor progression and metastasis (Hayward, 1989). Differentiation of the neoplastic B cell is blocked at the IgM-producing stage. The first event can be seen in the bursa a few weeks after infection by ALV as one or more transformed lymphoid follicles (termed a focal preneoplastic hyperplasia) in which the normal B cell components are replaced by proliferating B lymphoblasts. Some of the transformed follicles evidently regress, but one or more progress over a period of several months to frank neoplasia with metastasis to other organs such as the liver and spleen, leading to death of the chicken. The cells arising from one follicle are clonal but progression to neoplasia in several follicles leads to polyclonal tumors. During progression the neoplastic lymphoblasts become resistant to induced apoptotic cell death. Certain vaccinal strains of Marek’s disease virus (Serotype 2) have been observed, in the field and experimentally, to enhance the incidence of lymphoid leukosis (Bacon et al., 1989; Fadly and Witter, 1993). Transactivation of the ALV LTR by Marek’s disease virus products has been invoked (Tieber et al., 1990; Banders and Coussens, 1994), and it has been observed also that ALV-induced preneoplastic bursal cells are more susceptible to infection by the vaccine virus, which may make them less susceptible to apoptosis and more susceptible to progressive ALV-induced bursal lymphoma (reviewed by Neiman, 1994). A less common expression of infection by slowly transforming ALV is erythroid leukosis (erythroblastosis), a disease in which the c-erbB gene in an erythroid cell is activated (Fung et al., 1983). The bone marrow is largely replaced by proliferating erythroblasts, a leukemia develops, and the liver, spleen, and other organs become enlarged due to accumulations of intravascular erythroblasts. Erythroid leukosis is induced by high doses of slowly transforming ALV and the disease has a shorter latent period than lymphoid leukosis. Another generally uncommon disease caused by ALV is myeloid leukosis (myeloblastosis and myelocytomatosis) (Payne and Fadly, 1997). Cases generally occur sporadically in adult birds. Here a myeloid cell becomes transformed, there is often a severe leukemia, and the liver, spleen, and other organs become infiltrated by intravascular and extravascular myeloid cells. The molecular mechanism for induction of the naturally occurring disease is not well understood. The ALV have been isolated from such cases and used to transmit the disease experimentally, but usually such isolates, where they have been characterized, are found to have acquired a viral oncogene and are acutely transforming, as discussed later. Recently, however, an ALV, designated HPRS-103, which induces myelocytic myeloid leukosis, but which lacks a viral oncogene, has been isolated from meat-type chickens in which it is quite prevalent (Payne et al., 1991, 1992; Bai et al., 1995a). This virus causes a late
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PATHOGENESIS OF ALSV-INDUCED DISEASES
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onset disease and is assumed to induce myeloid leukosis by insertional mutagenesis. The cellular oncogene activated is not yet known. A variety of other tumors are also induced by the various strains of ALSV (reviewed by Beard, 1980; Payne and Fadly, 1997). These include myxosarcoma, histiocytic sarcoma, osteosarcoma, chondrosarcoma, hemangioma, various types of renal tumor, mesothelioma, hepatocarcinoma, granulosa cell tumor, pancreatic carcinoma, and the proliferative bone disorder, osteopetrosis. For the most part, the viral and cellular oncogenes involved in these tumors have not been elucidated.
Acutely Transforming ALV
ALV and Hematopoietic Cell Differentiation By virtue of their ability to rapidly transform cultured bone marrow and yolk sac cells in vitro, acutely transforming ALV have contributed greatly to studies on hematopoietic cell differentiation and the nature of the target cells for neoplastic transformation (reviewed by Graf and Beug, 1978; Moscovici and Gazzolo, 1987). Use of such viruses carrying various oncogenes has led to identification of the target cell(s) for each virus, the development of culture systems for studying such cells, and the role of the oncogene product in inducing the neoplastic state. Monoclonal antibodies developed against the transformed cells have been of value in identifying hematopoietic cell lineages and stages. Naturally occurring peptides have been found which regulate the differentiation of the various cell stages by binding to specific transmembrane receptors and activating intracellular signal transduction pathways. Phorbol esters have been shown to mimic such peptides and have been of value in differentiation studies. Most of the acutely transforming ALV stimulate cells of a particular lineage and stage. Thus, AMV, carrying myb, stimulates proliferation of myelomonocytic cells at the promyelocytic stage; AEV (with erbA and erbB) transforms the erythroblast; avian myelocytoma viruses (with myc) transform myelomonocytic cells at late, myelocytic and monocytic, stages of differentiation. The E26 virus, carrying myb and ets, is unusual in being multipotential in the cell lineage that it can stimulate. This virus can transform multipotential hematopoietic precursors that can differentiate into erythrocytes and thrombocytes and that can also be induced to differentiate into myeloblasts or eosinophils by treatment with phorbol
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Acutely transforming ALV have the same basic structure as slowly transforming virus, but in addition they have within their genome, in variable locations, one or sometimes two viral oncogenes. Genetic deletions within the structural genes also occur such that the oncogene-carrying virion is unable to replicate; it needs the presence of a nondefective ALV helper virus to complement the genetic defect. These ALV are termed acutely transforming because they can neoplastically transform their appropriate target cells, both in cell culture and in vivo, in a matter of a few days (reviewed by Graf and Beug, 1978; and Enrietto and Hayman, 1987). Some 15 avian viral oncogenes have been identified (reviewed by Rasheed, 1995). Viral oncogenes show sequence variation from the corresponding cellular counterpart, and their products may differ also. These genes, uncontrolled by normal regulatory processes, and their abnormal products, bring about changes in cell growth and differentiation, resulting in neoplasia. Oncogenes products are concerned with cell functions related to control of cell growth and differentiation. They mostly fall into four main classes: growth factors, growth factor receptors, nuclear factors, and signal transducers. The MC29, CMII, and OK10 strains of ALV carry the myc oncogene, which encodes transcription factors, and they induce tumors of the myelomonocytic series of cells. The BAI-A strain of avian myeloblastosis virus (AMV) carries myb, which encodes a transcription regulator, and induces a tumor of myeloblasts and promyelocytes. The H strain of avian erythroblastosis virus (AEV) induces erythroid leukosis and carries erbB, which encodes epidermal growth factor receptors. MH2 virus induces a tumor of a myelomonocytic stem cell and has two oncogenes, myc and mil: the myc gene transforms the target stem cell and the mil gene produces myelomonocytic growth factor necessary for the continued proliferation of the transformed cells. Other viruses possessing two oncogenes are the ES4 strain of AEV (erbA and erbB) and the E26 strain of AMV (myb and ets). Genes erbA and ets encode transcription factors. Acutely transforming AVL able to induce myeloid leukosis have been isolated when that disease is induced by the HPRS-103 strain of ALV
(Payne et al., 1993). Preliminary evidence suggests that they have acquired v-myc, making it likely that HPRS-103 itself activates c-myc. Several acutely transforming avian sarcoma viruses also occur. Rous sarcoma virus, the most extensively studied, has the viral oncogene src, the first oncogene to be discovered, which encodes a protein kinase. Fujinami and PRCII sarcoma viruses have fps (protein kinase), S13 has sea (growth factor receptor), UR2 has ros (insulin-like receptor), Y73 and Esh have yes (vinculin-like factor), and ASV-17 has jun (DNA binding protein). These viruses, with the exception of some strains of RSV, are genetically defective also and require a helper virus to replicate. These various acutely transforming viruses have, evidently, acquired their viral oncogene by transduction and modification of a cellular proto-oncogene during the integration of an ALV into the host genome and the induction of neoplasia by insertional mutagenesis. This transduction has been shown to occur experimentally during induction of erythroblastosis or sarcomas by slowly transforming ALV (Hihara et al., 1983; Wang and Hanafusa, 1988).
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esters (Graf et al., 1992; McNagny et al., 1992). Development of temperature sensitive mutants of E26, and of recombinant E26 viruses containing other oncogenes such as myc or erbA, have been other ways of manipulating the target cells for transformation. These virus-cell systems are contributing powerfully to understanding of hematopoietic cells differentiation at the molecular level.
Envelope Subgroups and Virus Receptors
The evolutionary relationship between the different env genes and their biological significance are not well understood. Little is known about env gene variability or mutation within subgroups. Subgroup A viruses appear, on the basis of cross-neutralization studies, to be closely related, whereas Subgroup B viruses appear to be more variable. More generally, the allocation over many years of ALV to one of the five env subgroups, with no finding of other subgroups, suggests genetic conservation. The env gene of Subgroup J ALV appears to have been acquired by a genetic recombination with virtually identical sequences belonging to the endogenous avian retrovirus (EAV) family of endogenous viruses. The env gene products from ALV appear to have no influence on the type of disease induced.
Exogenous and Endogenous ALV One the basis of the way in which they are transmitted naturally, ALV can be classified as exogenous or endogenous viruses (reviewed by Crittenden, 1981; Payne, 1987). The former spread as infectious virions, either vertically (congenitally) from dam to progeny through the egg, or horizontally from bird to bird. Viruses of Subgroups A, B, C, D and J spread in this way, and of these A, B and J occur commonly in the field; C and D appear to be rare. Endogenous viruses occur integrated into the genome of the germline of normal chickens and are transmitted genetically in a Mendelian way. Several families of endogenous viruses are recognized: the RAV-0 family of ev loci, the moderately repetitive EAV and ARTCH families, and the highly repetitive CR1 family (reviewed by Crittenden, 1991). The origin, evolutionary relationships and biological significance of these elements are not clearly understood. In evolutionary terms, the CR1 retrotransposon elements appear to be the most ancient and the ev genes the most recent. These types of elements are examples of retroelements (retroposons, retrotransposons) that are found in an extremely broad range of organisms, including fungi, plants, protozoa, and animals, and that are concerned with the mobility of genes within the genome of organisms. These elements are believed to be the evolutionary precursors of retroviruses; that is, genetic elements that have acquired the ability to exist as infectious entities outside of cells. Even so, it is considered that some endogenous viruses, such as the ev loci, may represent exogenous viruses that have become reintegrated on an evolutionary scale into the germline. Most endogenous viruses are genetically defective in that they do not possess the full complement of retroviral genes necessary for the production of infectious virions. However, some do and they give rise to Subgroup E ALV, of which RAV-0 is the prototype. Unlike viruses of the other subgroups, Subgroup E ALV do not induce neoplasms, evidently because the LTR has weak gene promoter activity. The biological value of endogenous viruses is not clear. It has been argued that because they persist they must be
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Work dating back some 25 yr placed ALV occurring in chickens into five envelope subgroups, A, B, C, D, and E (Weiss et al., 1982). More recently a sixth subgroup, J, represented by HPRS-103, has been recognized (Payne et al., 1991; Bai et al., 1995b). The subgroup reflects the genetic sequence of the env gene and the amino acid sequence of the gp85 surface (SU) envelope protein that is encoded. The SU protein determines the ability of the ALV to infect cells via specific virus receptors in the cell membrane, and is also the determinant of virusneutralizing antibodies produced by the host in response to infection posthatching. Sequence studies on the env gene from representative viruses of Subgroups A to E indicate that subgroup variability depends on several short regions: three variable regions, vr1, vr2, and vr3, and two larger host range regions, hr1 and hr2 (Bova et al., 1986). On the other hand, the HPRS-103 strain of Subgroup J, ALV, differs from viruses of Subgroups A to E by nucleotide changes occurring throughout the SU of its env gene (Bai et al., 1995b). However, envelope heterogeneity between Subgroup J isolates does appear to be clustered in the variable and host range regions described above (K. Venugopal, L. M. Smith, K. Howes and L. N. Payne, unpublished data). Elucidation of the host genetic control of cell receptors for ALV of Subgroups A to E coincided generally with discovery of the virus subgroups (reviewed by Crittenden, 1975; Payne, 1985). One stimulus for such work was the possibility of controlling ALV infection commercially by selection of genetically resistant stock. Three autosomal loci, tva, tvb, and tvc, with dominant susceptibility genes and recessive resistance genes, independently control susceptibility to Subgroup A, Subgroups B and D, and Subgroup C, respectively. There is disagreement about whether Subgroup E susceptibility is controlled by the same locus (tvb) that controls response to B and D, or by another locus, tve. Susceptibility of cells to infection by Subgroup E ALV is made more complex in some instances by blocking of the virus receptor by endogenous viral envelope. Genetic resistance in chickens to infection by Subgroup J ALV has not been recognized: all chicken strains are susceptible. In recent years, progress has been made in identifying the nature of the receptors to ALV. The receptor for Subgroup A is related to the low density lipoprotein receptor (Bates et al., 1993) and that for Subgroups B and D is a member of the tumor necrosis factor family (Brojatsch et al., 1996).
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of value. More specifically, the presence of ev2 or ev3 has been reported to protect birds from a non-neoplastic syndrome caused by infection with Subgroup A ALV (Crittenden et al., 1982, 1984). However, in certain circumstances they can be detrimental. Thus embryonic infection with RAV-0 causes a more persistent viremia and more neoplasms following infection with exogenous ALV, apparently due to depression of humoral immunity (Crittenden et al., 1987). Similarly, expression of EV21 ALV by the ev21 locus, which is linked with the sex-linked slow-feathering gene, K, on the Z chromosome, has a tolerizing effect on response to exogenous ALV, and has been associated with an increased incidence of lymphoid leukosis in the field and experimentally.
Although infection with exogenous ALV is widely prevalent in commercial flocks, mortality from the leukoses and other tumors is usually low, of the order of 1 to 2%. However, the significance of exogenous ALV infection began to be reassessed some 20 yr ago, following the discovery that non-neoplastic effects of subclinical infection could result in significant economic losses from suboptimal performance (reviewed by Gavora, 1987). Traits influenced unfavorably included age at sexual maturity, egg production, egg weight, fertility, hatchability, nonspecific mortality, and body weight. Such effects are of practical and theoretical importance to poultry geneticists and breeders because of the confounding effect on genetic traits. The economic losses and the effect on breeding stimulated renewed interest in control of ALV infections. Endogenous viruses can also affect production traits, by their interaction with exogenous ALV, and also directly if the endogenous virus is expressed in an infectious form (Gavora et al., 1991).
Epidemiology and Control of ALV Horizontal spread of exogenous ALV from bird to bird by contact normally leads to an immune response characterized by the development of virus-neutralizing antibodies (Payne, 1987). Sources of virus from infected birds are feces, saliva, and skin. Some birds infected in this way may become occasional shedders of ALV in their eggs and consequently transmitters of ALV to their progeny. In contrast, birds that are congenitally infected become immunologically tolerant to the virus, do not develop neutralizing antibodies, and have a persistent viremia. Hens so infected are persistent shedders of ALV in their eggs and transmitters of ALV to their progeny (Spencer et al., 1977). Infected cocks are generally considered not to transmit ALV to their progeny. Meconium from day-old congenitally infected chicks contains high concentrations of ALV and is an important source of virus for infecting hatch mates. Congenitally infected birds are more likely to develop neoplasia than birds infected by contact.
PATHOGENESIS OF REV-INDUCED DISEASES Reticuloendotheliosis virus is more closely related to mammalian retroviruses than to ALSV. The REV strains
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Influence of ALV on Production Traits
No vaccines have been developed for the control of ALV infection. Selection for genetic resistance to infection has been used by poultry breeding companies as a control measure but currently breeders mostly use schemes to eradicate ALV from their stock (Spencer, 1984). These schemes stem mainly from the work of Spencer et al. (1977), and are aimed at preventing vertical transmission of ALV from one generation to the next, and prevention of reinfection. The method uses the fact that hens that transmit ALV to their progeny can be identified by detecting ALV group-specific (gs) antigen in vaginal swabs or in their egg albumen, using an ELISA test, available commercially. Schemes for ALV eradication, for both egg-type and meat-type poultry, are applied by breeders primarily at the elite pure line level. Depending on the desired intensity of the eradication effort, the overall eradication scheme can involve a combination of a variety of procedures: 1) The essential procedure involves selection of fertile eggs for producing the next generation from hens negative for ALV shedding in tests on egg albumen and vaginal swabs, using the ELISA for gs antigen. Swab tests are usually applied a few weeks before birds come into lay; egg albumen tests are usually applied on the first eggs (often two) laid by the hen, and again when elite replacements are taken. 2) Hens may be tested for viremia just before coming into lay, discarding positive birds. 3) Chicks are hatched in isolation in small groups in wirefloored cages, avoiding manual sexing and vaccination of different pedigree groups with a common vaccination needle, to prevent mechanical spread of any residual infection. 4) The meconium of newly hatched chicks is tested for gs antigen, discarding positive dam groups. 5) ALV-free groups are reared in isolation. 6) Cocks are selected for freedom from ALV by testing cloacal swabs or semen for gs antigen. By use of such schemes in both egg and meat stock, breeders have been able to markedly reduce the prevalence of ALV infection in a few generations of testing (Okazaki et al., 1979; 1982; Payne and Howes, 1991). Complete eradication is more difficult and requires very extensive testing programs. There is evidence that congenital transmission of ALV can occur in the absence of detectable shedding of gs antigen (Ignjatovic, 1990). Use of PCR-based tests may prove of value here. Eradication from some lines has been found to be more difficult than from others. The presence of the ev21 locus slows eradication, apparently by making chicks more susceptible to posthatching ALV infection leading to viremic infections. The propensity of meat-type chicks to develop viremic infections after posthatching infection with Subgroup J ALV may also hinder eradication.
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can cause a variety of non-neoplastic lesions in chickens and ducks, collectively designated as the runting disease syndrome, two types of chronic lymphomatous disease in chickens and other poultry, and an acute reticulum cell neoplasm (reticuloendotheliosis) (reviewed by Bagust, 1993; McDougall, 1993; Witter, 1997).
Nondefective REV
Replication-Defective Strain T REV Strain T REV was isolated in 1958 from a turkey with gross leukotic lesions. Strain T has genetic deletions in the gag, pol, and env regions, and a substitution in the env region identified as the transforming gene, v-rel, most probably derived from the cellular oncogene c-rel present in normal turkey cells, and requires a nondefective REV as a helper virus to allow it to replicate. Strain T REV differs from other REV by being, like acutely transforming ALV, rapidly and highly oncogenic in chickens in vivo and in vitro. Strain T virus causes death of infected chicks in 1 to 3 wk from widespread proliferation of primitive mesenchymal or reticuloendothelial cells; there is probably more than one type of target cell, including both immature B cells and T cells. The so-called acute reticulum cell neoplasm (reticuloendotheliosis) induced is an experimental disease of chickens, and has no recognized naturally occurring counterpart.
Epidemiology and Control Serological evidence of REV infection is detected in a significant proportion of commercial layer, broiler, and turkey flocks in the U.S., usually with no disease or
deleterious effect on performance. Occasionally, however, naturally occurring lymphomatous disease associated with REV has been observed in turkeys, chickens, and other species. The REV is transmitted both horizontally by contact with infected chickens and turkeys and vertically from tolerantly infected chicken and turkey dams. Vertical transmission can also occur from infected male chickens and turkeys. There is no evidence for genetic transmission of REV. Because of the usually sporadic and subclinical nature of REV infections, no control procedures have been necessary commercially; however, it is probable that eradication could be achieved by prevention of vertical transmission through testing egg albumen samples for REV gs antigen, testing males, and rearing progeny in isolation. An intriguing recent finding has been evidence for the presence of REV genetic sequences integrated on occasions into Marek’s disease virus genome (reviewed by Isfort et al., 1994). This finding raises the possibility that the pathogenicity of Marek’s disease virus could be modified, and also that REV (and perhaps other retrovirus genomes) could be transmitted within the Marek’s disease virus genome. The prevalence of such occurrences, and their biological significance, remains to be determined.
PATHOGENESIS OF LPDV-RELATED DISEASE Lymphoproliferative disease of turkeys was first described in 1974 in the U.K. and 2 yr later in Israel (reviewed by McDougall, 1993; Biggs, 1997). Studies on the virus have been handicapped by lack of an in vitro culture system and virus characterization has depended on virus prepared from tissues of infected turkeys. An evolutionary relationship between the pol genes of LPDV and ALSV has been suggested, but apart from that LPDV has been considered to be unrelated to ALSV and REV. Sequences specific to LPDV are not present in normal turkey cells, indicating that the virus is not endogenous in turkeys. The natural disease occurs in turkeys between 7 and 18 wk of age, characterized by enlarged spleen and liver and widespread infiltration of tissues by lymphocytes, lymphoblasts, plasma cells, and reticulum cells. Experimentally, lymphoproliferative lesions are first seen in the spleen and thymus 14 d after infection of 4-wk-old turkeys. The incidence of the disease is higher in poults infected at 4 wk than at 1 d of age and is characterized by an unusual persistent viremia, immunosuppression, and hypergammaglobulinemia. The nature of this lymphoproliferative disease remains to be determined. LPDV can spread by contact, but otherwise little is known about the epidemiology of the disease. Control has been by elimination of infected turkey strains.
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Like ALV, nondefective REV are simple retroviruses with gag, pol, and env genes. They fall into a single serotype, with three antigenic subtypes. In chickens, REV can, experimentally, cause a lymphomatous disease with a long latent period that is pathologically very similar to lymphoid leukosis caused by slowly transforming ALV. The REV-induced tumor originates in the cloacal bursa, with transformation of IgM-bearing B cells, and later spreads to the liver and other organs. Lymphoma induction is associated with integration of REV proviral genome adjacent to the c-myc gene. A second type of chronic lymphoma in chickens occurs experimentally more rapidly, by 6 wk. The second type is a T cell neoplasm, again associated with activation of cmyc by insertional mutagenesis, and involves the thymus, liver, spleen, heart, and peripheral nerves, but not the cloacal bursa. In turkeys, REV causes a lymphomatous disease, naturally and experimentally; chronic lymphomas caused by REV have also been described in ducks, geese, pheasants, and quail. The nature and molecular basis for these lymphomas in species other than chickens are not well understood.
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CONCLUSIONS
REFERENCES Bacon, L. D., R. L. Witter, and A. M. Fadly, 1989. Augmentation of retrovirus-induced lymphoid leukosis by Marek’s
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Infections by avian retroviruses show features that set them apart from other avian virus diseases. Central is the occurrence of vertical transmission, which maintains the infection from one generation to the next, and which provides a source of early contact exposure of uninfected chicks. In consequence, vaccination has not been seen as a preventive measure, and in fact in limited studies candidate vaccines have not been effective. Over the past century, control has been by adoption of principles of good husbandry (to reduce contact spread), genetic selection against tumor incidence or virus infection, and most recently by schemes for eradicating the infections from breeding stock. This last provides the ideal approach, but it is demanding in resources and technology. For the most part, these measures have controlled infection and disease adequately. Nevertheless, retroviruses remain a constant and unpredictable threat, as recent outbreaks of hemangiosarcomas in Israel, and currently myelocytomatosis in several countries, remind us. In the latter instance, a new virus, which appears to be a recombinant involving endogenous viral sequences, is responsible, highlighting the need to understand relationships between exogenous and the ubiquitous endogenous viruses. Furthermore, new practices introduced by the poultry industry may lead to unexpected problems, as exemplified by the occurrence in the field of enhancement of lymphoid leukosis losses by the endogenous EV21 virus, associated with the slow-feathering gene, and of the same disease by use of certain Marek’s disease vaccines. Subsequent elegant research has not only contributed to an understanding of the scientific basis of these phenomena, but has revealed significant new scientific principles. A lesson is that it is likely that there are other unrecognized factors in the field that influence tumor incidence that need to be identified and understood. Within the past 20 yr or so the era of molecular biology has been entered, the powerful techniques of which have touched every aspect of the study of avian retroviruses. Much of the work done has come from biomedical laboratories in which these viruses and diseases are studied as models of viral oncogenesis; the discovery of oncogenes coming from such work has justified this approach. An exciting historical account of this recent work is provided by Weinberg (1997). However, knowledge so gained has also been applied beneficially to problems more related to the poultry industry. Even so, the flow of knowledge has not been entirely one-way. What can be expected is that this knowledge will lead to new ways of controlling retroviruses and the associated neoplastic diseases. Ellermann and Bang (1908), and Rous (1910), the originators of avian tumor virus research, would be satisfied with the progress being made.
disease herpesvirus in white leghorn chickens. J. Virol. 63: 504–512. Bagust, T. J., 1993. Reticuloendotheliosis virus. Pages 437–454 in: Virus Infections of Birds. J. B. McFerran and M. S. McNulty, ed. Elsevier, Amsterdam, The Netherlands. Bai, J., L. N. Payne, and M. A. Skinner, 1995a. HPRS-103 (exogenous avian leukosis virus, subgroup J) has an env gene related to those of endogenous elements EAV-0 and E51 and an E element found previously only in sarcoma viruses. J. Virol. 69:779–784. Bai, J., K. Howes, L. N. Payne, and M. A. Skinner, 1995b. Sequence of host-range determinants in the env gene of a full-length infectious proviral clone of exogenous avian leukosis virus HPRS-103 confirms that it represents a new subgroup (designated J). J. Gen. Virol. 76:181–187. Banders, U. T., and P. M. Coussens, 1994. Interactions between Marek’s disease virus encoded or induced factors and the Rous sarcoma virus long terminal repeat promoter. Virology 199:1–10. Bates, P., J. A. Young, and H. E. Varmus, 1993. A receptor for subgroup A Rous sarcoma virus is related to the low density lipoprotein receptor. Cell 74:1043–1051. Beard, J. W., 1980. Biology of avian oncornaviruses. Pages 55–57 in: Viral Oncology. G. Klein, ed. Raven Press, New York, NY. Biggs, P. M., 1997. Lymphoproliferative disease of turkeys. Pages 485–489 in: Diseases of Poultry. 10th ed. B. W. Calnek, H. J. Barnes, C. W. Beard, L. R. McDougald, and Y. M. Saif, ed. Iowa State University Press, Ames, IA. Biggs, P. M., J. S. McDougall, J. A. Frazier, and B. S. Milne, 1978. Lymphoproliferative disease of turkeys. 1. Clinical aspects. Avian Pathol. 7:131–139. Bova, C. A., J. P. Manfredi, and R. Swanstrom, 1986. Env genes of avian retroviruses: nucleotide sequence and molecular recombinants define host range determinants. Virology 152:343–354. Brojatsch, J., J. Naughton, M. M. Rolls, K. Zingler, and J.A.T. Young, 1996. CAR1, a TNFR-related protein, is a cellular receptor for cytopathic avian leukosis-sarcoma viruses and mediates apoptosis. Cell 87:845–855. Coffin, J. M., 1992. Structure and classification of retroviruses. Pages 19–49 in: The Retroviridae. Vol. 1. J. Levy, ed. Plenum Press, New York, NY. Crittenden, L. B., 1975. Two levels of genetic resistance to lymphoid leukosis. Avian Dis. 19:281–292. Crittenden, L. B., 1981. Exogenous and endogenous leukosis virus genes—a review. Avian Pathol. 10:101–112. Crittenden, L. B., 1991. Retroviral elements in the genome of the chicken: Implications for poultry genetics and breeding. Cri. Rev. Poult. Biol. 3:73–109. Crittenden, L. B., A. M. Fadly, and E. J. Smith, 1982. Effect of endogenous leukosis virus genes on response to infection with avian leukosis and reticuloendotheliosis viruses. Avian Dis. 26:279–294. Crittenden, L. B., E. J. Smith, and A. M. Fadly, 1984. Influence of endogenous viral (ev) gene expression and strain of exogenous avian leukosis virus (ALV) on mortality and ALV infection and shedding in chickens. Avian Dis. 28: 1037–1056. Crittenden, L. B., S. McMahon, M. S. Halpern, and A. M. Fadly, 1987. Embryonic infection with the endogenous avian leukosis virus Rous associated virus-0 alters
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Moscovici, C., and L. Gazzolo, 1987. Virus-cell interactions of avian sarcoma and defective leukemia viruses. Pages 153–169 in: Avian Leukosis. G. F. De Boer, ed. Martinus Nijhoff Publishing, Boston, MA. Neiman, P., 1994. Retrovirus-induced B cell neoplasia in the Bursa of Fabricius. Adv. Immunol. 56:467–484. Okazaki, W., B. R. Burmester, A. M. Fadly, and W. B. Chase, 1979. An evaluation of methods for eradication of avian leukosis virus from a commercial breeder flock. Avian Dis. 23:688–697. Okazaki, W., A. M. Fadly, L. B. Crittenden, and W. B. Chase, 1982. The effectiveness of selection for reduced avian leukosis virus shedding in different chicken strains. Avian Dis. 26:612–617. Payne, L. N., 1985. Genetics of cell receptors for avian retroviruses. Pages 1–16 in: Poultry Genetics and Breeding, W. G. Hill, J. M. Manson, and D. Hewitt, ed. British Poultry Science, Harlow, UK. Payne, L. N., 1987. Epizootiology of avian leukosis virus infections. Pages 47–75 in: Avian Leukosis. G. F. De Boer, ed. Martinus Nijhoff Publishing, Boston, MA. Payne, L. N., 1992. Biology of avian retroviruses. Pages 299–404 in: The Retroviridae. Vol. 1. J. Levy, ed. Plenum Press, New York, NY. Payne, L. N., and K. Howes, 1991. Eradication of exogenous avian leukosis virus from commercial layer breeder lines. Vet. Rec. 128:8–11. Payne, L. N., and A. M. Fadly, 1997. Leukosis/sarcoma group. Pages 414–466 in: Diseases of Poultry. 10th ed. B. W. Calnek, H. J. Barnes, C. W. Beard, L. R. McDougald, and Y. M. Saif, ed. Iowa State University Press, Ames, IA. Payne, L. N., S. R. Brown, N. Bumstead, K. Howes, J. A. Frazier, and M. E. Thouless, 1991. A novel subgroup of exogenous avian leukosis virus in chickens. J. Gen. Virol. 72:801–807. Payne, L. N., A. M. Gillespie, and K. Howes, 1992. Myeloid leukaemogenicity and transmission of the HPRS-103 strain of avian leukosis virus. Leukemia 6:1167–1176. Payne, L. N., A. M. Gillespie, and K. Howes, 1993. Recovery of acutely transforming viruses from myeloid leukosis induced by the HPRS-103 strain of avian leukosis virus. Avian Dis. 37:438–450. Purchase, H. G., 1987. The pathogenesis and pathology of neoplasms caused by avian leukosis viruses. Pages 171–196 in: Avian Leukosis. G. F. De Boer, ed. Martinus Nijhoff Publishing, Boston, MA. Rasheed, S., 1995. Retroviruses and oncogenes. Pages 293–408 in: The Retroviridae. Vol. 4. J. Levy, ed. Plenum Press, New York, NY. Rous, P., 1910. A transmissible avian neoplasm. (Sarcoma of the common fowl). J. Exp. Med. 12:696–705. Spencer, J. L., 1984. Progress towards eradication of lymphoid leukosis viruses: a review. Avian Pathol. 13:599–619. Spencer, J. L., L. B. Crittenden, B. R. Burmester, W. Okazaki, and R. L. Witter, 1977. Lymphoid leukosis: interrelations among virus infections in hens, eggs, embryos and chicks. Avian Dis. 21:331–345. Theilen, G. H., R. F. Zeigel, and M. J. Twiehaus, 1966. Biological studies with RE virus (strain T) that induces reticuloendotheliosis in turkeys, chickens and Japanese quail. J. Natl. Cancer Inst. 37:731–743. Tieber, V. L., L. L. Zalinskis, R. F. Silva, A. Finkelstein, and P. M. Coussens, 1990. Transactivation of the Rous sarcoma
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responses to exogenous avian leukosis virus infection. J. Virol. 61:722–725. De Boer, G. F., ed. 1987. Avian Leukosis. Martinus Nijhoff Publishing, Boston, MA. Ellermann, V., and O. Bang, 1908. Experimentelle Leukamie bei Huhnern. Zentralbl. Bakteriol. Parasitenkd. Infectionskr. Hyg. Abt. Orig. 46:595–609. Enrietto, P. J., and M. J. Hayman, 1987. Structure and virusassociated oncogenes of avian sarcoma and leukemia virus. Pages 29–46 in: Avian Leukosis. G. F. De Boer, ed. Martinus Nijhoff Publishing, Boston, MA. Fadly, A. M., and R. L. Witter, 1993. Effects of age at infection with serotype 2 Marek’s disease virus on enhancement of avian leukosis virus-induced lymphomas. Avian Pathol. 22:565–576. Fung, Y.-K., W. G. Lewis, L. B. Crittenden, and H.-J. Kung, 1983. Activation of the cellular oncogene c-erbB by LTR insertion: Molecular basis for the induction of erythroblastosis by avian leukosis virus. Cell 33:357–368. Gavora, J. S., 1987. Influence of avian leukosis virus infection on production and mortality and the role of genetic selection in the control of lymphoid leukosis. Pages 241–260 in: Avian Leukosis, G. F. De Boer, ed. Martinus Nijhoff Publishing, Boston, MA. Gavora, J. S., U. Kuhnlein, L. B. Crittenden, J. L. Spencer, and M. P. Sabour, 1991. Endogenous viral genes: association with reduced egg production rate, and egg size in White Leghorns. Poultry Sci. 70:618–623. Graf, T., and H. Beug, 1978. Avian leukemia viruses. Interactions with their target cells in vivo and in vitro. Biochim. Biophys. Acta 516:269–299. Graf, T., K. McNagny, G. Brady, and J. Frampton, 1992. Chicken “erythroid” cells transformed by the Gag-MybEts-encoding E26 leukemia virus. Cell 70:201–213. Hanafusa, T., H. Hanafusa, C. E. Metroka, W. S. Hayward, C. W. Rettenmier, R. C. Sawyer, R. M. Dougherty, and H. S. Di Stefano, 1976. Pheasant virus: New class of ribodeoxyvirus. Proc. Natl. Acad. Sci. U.S.A. 73:1333–1337. Hayward, W. S., 1989. Multiple stages in avian leukosis virusinduced B cell lymphoma. Pages 57–65 in: Retroviruses and Disease. H. Hanafusa, A. Pinter, and M. E. Pullman, ed. Academic Press, San Diego, CA. Hihara, H., H. Yamamoto, H. Shimohira, K. Arai, and T. Shimizu, 1983. Avian erythroblastosis virus isolated from chick erythroblastosis induced by lymphatic leukemia virus subgroup A. J. Natl. Cancer Inst. 70:891–897. Ignjatovic, J., 1990. Congenital transmission of avian leukosis virus in the absence of detectable shedding of group specific antigen. Aust. Vet. J. 67:299–301. Isfort, R. J., R. Witter, and H.-J. Kung, 1994. Retrovirus insertion into herpesviruses. Trends in Microbiol. 2: 174–177. Kung, H.-J., and N. J. Maihle, 1987. Molecular basis of oncogenesis by non-acute avian retroviruses. Pages 77–99 in: Avian Leukosis. G. F. De Boer, ed. Martinus Nijhoff Publishing, Boston, MA. McDougall, J. S., 1993. Tumour viruses of turkeys. Pages 455–463 in: Virus Infections of Birds. J. B. McFerran and M. S. McNulty, ed. Elsevier, Amsterdam, The Netherlands. McNagny, K. M., F. Lim, S. Grieser, and T. Graf, 1992. Cell surface proteins of chicken hematopoietic progenitors, thrombocytes and eosinophils detected by novel monoclonal antibodies. Leukemia 6:975–984.
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virus long terminal repeat promoter by Marek’s disease virus. Virology 179:719–727. Wang, L.-H., and H. Hanafusa, 1988. Avian sarcoma viruses. Virus Res. 9:159–203. Weinberg, R. A., 1997. Racing to the Beginning of the Road. The Search for the Origin of Cancer. Bantam Press, London, UK.
Weiss, R., N. Teich, H. Varmus, and J. Coffin, 1982. RNA Tumor Viruses. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Witter, R. L., 1997. Reticuloendotheliosis. Pages 467–484 in: Disease of Poultry. 10th ed. B. W. Calnek, H. J. Barnes, C. W. Beard, L. R. McDougald, and Y. M. Saif, ed. Iowa State University Press, Ames, IA.
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(Key words: chicken, oncogenesis, retrovirus, tumors, turkey) 1998 Poultry Science 77:1204–1212
INTRODUCTION It is now some 90 yr since Ellermann and Bang (1908), working in Copenhagen, and Rous (1910), in New York, showed that leukemia (leukosis) and sarcomas in the domestic fowl have a viral etiology. Over the following decades, diseases of the so-called avian leukosis complex became the major cause of mortality in poultry in many countries, which stimulated extensive investigation in many veterinary laboratories in attempts to try to understand and control these conditions. At the same time, many medical workers worked with Rous sarcoma virus (RSV) and the avian leukosis viruses (ALV) as model systems with which to study the role of viruses in the causation of tumors. As a consequence, an enormous body of literature has been accumulated, and probably more is known about the avian leukosis/sarcoma virus
Received for publication August 3, 1997. Accepted for publication February 17, 1998. 1To whom correspondence should be addressed.
(ALSV) group of viruses and the diseases they cause than about any other avian pathogen. We now know that the viruses concerned are retroviruses, that is, RNA viruses that replicate via a DNA proviral stage linearly present in the host genome, by virtue of the presence in the viral genome of a pol gene that encodes the enzyme reverse transcriptase necessary for the transcription of RNA to DNA. The ALSV species of retroviruses are currently classified in a genus termed “ALV-related” in the family Retroviridae (Coffin, 1992). Another species of avian retrovirus, reticuloendotheliosis virus (REV), discovered in turkeys in 1958 (Theilen et al., 1966), is placed in the subgenus Reticuloendotheliosis, of the genus MLV-related [reflecting, unexpectedly, a relation-
Abbreviation Key: AEV = avian erythroblastosis virus; ALSV = avian leukosis/sarcoma virus; AMV = avian myeloblastosis virus; EAV = endogenous avian retrovirus; gs = group-specific; LPDV = lymphoproliferative disease virus; LTR = long terminal repeat; MLV = murine leukemia virus; REV = reticuloendotheliosis virus; RSV = Rous sarcoma virus; SU = gp85 surface.
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ABSTRACT Three species of avian retrovirus cause disease in poultry: the avian leukosis/sarcoma virus (ALSV), reticuloendotheliosis virus (REV), and lymphoproliferative disease virus (LPDV) of turkeys. The ALSV can be classified as slowly transforming viruses, which lack a viral oncogene, and acutely transforming viruses, which possess a viral oncogene. Slowly transforming viruses induce late onset leukoses of the B cell lymphoid, erythroid, and myeloid cell lineages, and other tumors, by viral promoter insertion into the genome of a host cell and activation of a cellular protooncogene. The various acutely transforming leukemia and sarcoma viruses induce leukotic or other tumors rapidly and carry one or another (sometimes two) viral oncogenes, of which some 15 have been identified. The ALSV fall into six envelope subgroups, A through E, and the recently recognized J subgroup, which induces myeloid leukosis. With the exception of Subgroup E viruses, these viruses spread vertically and horizontally as infectious virions, and are termed exogenous viruses. Subgroup E viruses are usually spread genetically as
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ship with murine leukemia virus (MLV)]. Two other species of avian retrovirus, both unrelated to ALV and REV, have also been described: lymphoproliferative disease virus of turkeys (LPDV; Biggs et al., 1978) and the little studied pheasant type C oncoviruses (Hanafusa et al., 1976). These two species have yet to be placed in Coffin’s “new taxonomy”. Many research reviews and text-book accounts of these avian retroviruses exist; recent examples including De Boer (1987), Payne (1992), and Payne and Fadly (1997). The present article will focus particularly on the pathogenesis and control of avian retrovirus-induced disease, with emphasis on areas of current research interest of relevance to the poultry industry.
Avian leukosis/sarcoma viruses induce leukoses affecting the erythroid, lymphoid, and myeloid series of hematopoietic cells, and a number of solid tumors, including those affecting cells of the mesenchyme, kidney, ovary, testis, liver, pancreas, and nervous system (reviewed by Beard, 1980; Purchase, 1987; Payne and Fadly, 1997). Significant progress has been made in understanding the molecular basis for the induction of a number of these conditions. Two types of ALV are recognized, slowly and acutely transforming, and their genetic makeup is known.
Slowly Transforming ALV Slowly transforming ALV are simple retroviruses, possessing the structural genes, gag, encoding the internal structural proteins of the virion; pol, encoding the RNAdependent DNA polymerase (reverse transcriptase); and env, encoding the viral envelope. They are arranged in the order 5′gag-pol-env3′. In the RNA form of the virus, they are flanked by controlling sequences and these form the long terminal repeat (LTR) sequences in the proviral DNA form. These viruses are termed slowly transforming because the tumors they induce are late in onset after infection of the chicken. It is known that these viruses induce lymphoid leukosis and erythroid leukosis (erythroblastosis) by insertional mutagenesis in which ALV genome with its LTR region becomes genetically integrated just upstream, downstream, or within a cellular proto-oncogene of the host. The cellular proto-oncogene becomes activated by the promoter or enhancer sequence of the LTR, leading to abnormal expression of the oncogene and to neoplasia. Differences in LTR sequences and the presence of specific LTR binding proteins are believed to determine the type of cell that is transformed. The commonest neoplasm induced by slowly transforming ALV is lymphoid leukosis. In this disease, the cmyc gene (or also c-myb experimentally) in a bursal lymphoid cell (B cell) is activated (reviewed by Kung and Maihle, 1987; Neiman, 1994). The tumor cell nuclei show
increased amounts of 62 kd Myc phosphoprotein. B Cell lymphomagenesis is a multi-stage event, with activation of other cellular oncogenes leading to tumor progression and metastasis (Hayward, 1989). Differentiation of the neoplastic B cell is blocked at the IgM-producing stage. The first event can be seen in the bursa a few weeks after infection by ALV as one or more transformed lymphoid follicles (termed a focal preneoplastic hyperplasia) in which the normal B cell components are replaced by proliferating B lymphoblasts. Some of the transformed follicles evidently regress, but one or more progress over a period of several months to frank neoplasia with metastasis to other organs such as the liver and spleen, leading to death of the chicken. The cells arising from one follicle are clonal but progression to neoplasia in several follicles leads to polyclonal tumors. During progression the neoplastic lymphoblasts become resistant to induced apoptotic cell death. Certain vaccinal strains of Marek’s disease virus (Serotype 2) have been observed, in the field and experimentally, to enhance the incidence of lymphoid leukosis (Bacon et al., 1989; Fadly and Witter, 1993). Transactivation of the ALV LTR by Marek’s disease virus products has been invoked (Tieber et al., 1990; Banders and Coussens, 1994), and it has been observed also that ALV-induced preneoplastic bursal cells are more susceptible to infection by the vaccine virus, which may make them less susceptible to apoptosis and more susceptible to progressive ALV-induced bursal lymphoma (reviewed by Neiman, 1994). A less common expression of infection by slowly transforming ALV is erythroid leukosis (erythroblastosis), a disease in which the c-erbB gene in an erythroid cell is activated (Fung et al., 1983). The bone marrow is largely replaced by proliferating erythroblasts, a leukemia develops, and the liver, spleen, and other organs become enlarged due to accumulations of intravascular erythroblasts. Erythroid leukosis is induced by high doses of slowly transforming ALV and the disease has a shorter latent period than lymphoid leukosis. Another generally uncommon disease caused by ALV is myeloid leukosis (myeloblastosis and myelocytomatosis) (Payne and Fadly, 1997). Cases generally occur sporadically in adult birds. Here a myeloid cell becomes transformed, there is often a severe leukemia, and the liver, spleen, and other organs become infiltrated by intravascular and extravascular myeloid cells. The molecular mechanism for induction of the naturally occurring disease is not well understood. The ALV have been isolated from such cases and used to transmit the disease experimentally, but usually such isolates, where they have been characterized, are found to have acquired a viral oncogene and are acutely transforming, as discussed later. Recently, however, an ALV, designated HPRS-103, which induces myelocytic myeloid leukosis, but which lacks a viral oncogene, has been isolated from meat-type chickens in which it is quite prevalent (Payne et al., 1991, 1992; Bai et al., 1995a). This virus causes a late
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PATHOGENESIS OF ALSV-INDUCED DISEASES
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onset disease and is assumed to induce myeloid leukosis by insertional mutagenesis. The cellular oncogene activated is not yet known. A variety of other tumors are also induced by the various strains of ALSV (reviewed by Beard, 1980; Payne and Fadly, 1997). These include myxosarcoma, histiocytic sarcoma, osteosarcoma, chondrosarcoma, hemangioma, various types of renal tumor, mesothelioma, hepatocarcinoma, granulosa cell tumor, pancreatic carcinoma, and the proliferative bone disorder, osteopetrosis. For the most part, the viral and cellular oncogenes involved in these tumors have not been elucidated.
Acutely Transforming ALV
ALV and Hematopoietic Cell Differentiation By virtue of their ability to rapidly transform cultured bone marrow and yolk sac cells in vitro, acutely transforming ALV have contributed greatly to studies on hematopoietic cell differentiation and the nature of the target cells for neoplastic transformation (reviewed by Graf and Beug, 1978; Moscovici and Gazzolo, 1987). Use of such viruses carrying various oncogenes has led to identification of the target cell(s) for each virus, the development of culture systems for studying such cells, and the role of the oncogene product in inducing the neoplastic state. Monoclonal antibodies developed against the transformed cells have been of value in identifying hematopoietic cell lineages and stages. Naturally occurring peptides have been found which regulate the differentiation of the various cell stages by binding to specific transmembrane receptors and activating intracellular signal transduction pathways. Phorbol esters have been shown to mimic such peptides and have been of value in differentiation studies. Most of the acutely transforming ALV stimulate cells of a particular lineage and stage. Thus, AMV, carrying myb, stimulates proliferation of myelomonocytic cells at the promyelocytic stage; AEV (with erbA and erbB) transforms the erythroblast; avian myelocytoma viruses (with myc) transform myelomonocytic cells at late, myelocytic and monocytic, stages of differentiation. The E26 virus, carrying myb and ets, is unusual in being multipotential in the cell lineage that it can stimulate. This virus can transform multipotential hematopoietic precursors that can differentiate into erythrocytes and thrombocytes and that can also be induced to differentiate into myeloblasts or eosinophils by treatment with phorbol
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Acutely transforming ALV have the same basic structure as slowly transforming virus, but in addition they have within their genome, in variable locations, one or sometimes two viral oncogenes. Genetic deletions within the structural genes also occur such that the oncogene-carrying virion is unable to replicate; it needs the presence of a nondefective ALV helper virus to complement the genetic defect. These ALV are termed acutely transforming because they can neoplastically transform their appropriate target cells, both in cell culture and in vivo, in a matter of a few days (reviewed by Graf and Beug, 1978; and Enrietto and Hayman, 1987). Some 15 avian viral oncogenes have been identified (reviewed by Rasheed, 1995). Viral oncogenes show sequence variation from the corresponding cellular counterpart, and their products may differ also. These genes, uncontrolled by normal regulatory processes, and their abnormal products, bring about changes in cell growth and differentiation, resulting in neoplasia. Oncogenes products are concerned with cell functions related to control of cell growth and differentiation. They mostly fall into four main classes: growth factors, growth factor receptors, nuclear factors, and signal transducers. The MC29, CMII, and OK10 strains of ALV carry the myc oncogene, which encodes transcription factors, and they induce tumors of the myelomonocytic series of cells. The BAI-A strain of avian myeloblastosis virus (AMV) carries myb, which encodes a transcription regulator, and induces a tumor of myeloblasts and promyelocytes. The H strain of avian erythroblastosis virus (AEV) induces erythroid leukosis and carries erbB, which encodes epidermal growth factor receptors. MH2 virus induces a tumor of a myelomonocytic stem cell and has two oncogenes, myc and mil: the myc gene transforms the target stem cell and the mil gene produces myelomonocytic growth factor necessary for the continued proliferation of the transformed cells. Other viruses possessing two oncogenes are the ES4 strain of AEV (erbA and erbB) and the E26 strain of AMV (myb and ets). Genes erbA and ets encode transcription factors. Acutely transforming AVL able to induce myeloid leukosis have been isolated when that disease is induced by the HPRS-103 strain of ALV
(Payne et al., 1993). Preliminary evidence suggests that they have acquired v-myc, making it likely that HPRS-103 itself activates c-myc. Several acutely transforming avian sarcoma viruses also occur. Rous sarcoma virus, the most extensively studied, has the viral oncogene src, the first oncogene to be discovered, which encodes a protein kinase. Fujinami and PRCII sarcoma viruses have fps (protein kinase), S13 has sea (growth factor receptor), UR2 has ros (insulin-like receptor), Y73 and Esh have yes (vinculin-like factor), and ASV-17 has jun (DNA binding protein). These viruses, with the exception of some strains of RSV, are genetically defective also and require a helper virus to replicate. These various acutely transforming viruses have, evidently, acquired their viral oncogene by transduction and modification of a cellular proto-oncogene during the integration of an ALV into the host genome and the induction of neoplasia by insertional mutagenesis. This transduction has been shown to occur experimentally during induction of erythroblastosis or sarcomas by slowly transforming ALV (Hihara et al., 1983; Wang and Hanafusa, 1988).
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esters (Graf et al., 1992; McNagny et al., 1992). Development of temperature sensitive mutants of E26, and of recombinant E26 viruses containing other oncogenes such as myc or erbA, have been other ways of manipulating the target cells for transformation. These virus-cell systems are contributing powerfully to understanding of hematopoietic cells differentiation at the molecular level.
Envelope Subgroups and Virus Receptors
The evolutionary relationship between the different env genes and their biological significance are not well understood. Little is known about env gene variability or mutation within subgroups. Subgroup A viruses appear, on the basis of cross-neutralization studies, to be closely related, whereas Subgroup B viruses appear to be more variable. More generally, the allocation over many years of ALV to one of the five env subgroups, with no finding of other subgroups, suggests genetic conservation. The env gene of Subgroup J ALV appears to have been acquired by a genetic recombination with virtually identical sequences belonging to the endogenous avian retrovirus (EAV) family of endogenous viruses. The env gene products from ALV appear to have no influence on the type of disease induced.
Exogenous and Endogenous ALV One the basis of the way in which they are transmitted naturally, ALV can be classified as exogenous or endogenous viruses (reviewed by Crittenden, 1981; Payne, 1987). The former spread as infectious virions, either vertically (congenitally) from dam to progeny through the egg, or horizontally from bird to bird. Viruses of Subgroups A, B, C, D and J spread in this way, and of these A, B and J occur commonly in the field; C and D appear to be rare. Endogenous viruses occur integrated into the genome of the germline of normal chickens and are transmitted genetically in a Mendelian way. Several families of endogenous viruses are recognized: the RAV-0 family of ev loci, the moderately repetitive EAV and ARTCH families, and the highly repetitive CR1 family (reviewed by Crittenden, 1991). The origin, evolutionary relationships and biological significance of these elements are not clearly understood. In evolutionary terms, the CR1 retrotransposon elements appear to be the most ancient and the ev genes the most recent. These types of elements are examples of retroelements (retroposons, retrotransposons) that are found in an extremely broad range of organisms, including fungi, plants, protozoa, and animals, and that are concerned with the mobility of genes within the genome of organisms. These elements are believed to be the evolutionary precursors of retroviruses; that is, genetic elements that have acquired the ability to exist as infectious entities outside of cells. Even so, it is considered that some endogenous viruses, such as the ev loci, may represent exogenous viruses that have become reintegrated on an evolutionary scale into the germline. Most endogenous viruses are genetically defective in that they do not possess the full complement of retroviral genes necessary for the production of infectious virions. However, some do and they give rise to Subgroup E ALV, of which RAV-0 is the prototype. Unlike viruses of the other subgroups, Subgroup E ALV do not induce neoplasms, evidently because the LTR has weak gene promoter activity. The biological value of endogenous viruses is not clear. It has been argued that because they persist they must be
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Work dating back some 25 yr placed ALV occurring in chickens into five envelope subgroups, A, B, C, D, and E (Weiss et al., 1982). More recently a sixth subgroup, J, represented by HPRS-103, has been recognized (Payne et al., 1991; Bai et al., 1995b). The subgroup reflects the genetic sequence of the env gene and the amino acid sequence of the gp85 surface (SU) envelope protein that is encoded. The SU protein determines the ability of the ALV to infect cells via specific virus receptors in the cell membrane, and is also the determinant of virusneutralizing antibodies produced by the host in response to infection posthatching. Sequence studies on the env gene from representative viruses of Subgroups A to E indicate that subgroup variability depends on several short regions: three variable regions, vr1, vr2, and vr3, and two larger host range regions, hr1 and hr2 (Bova et al., 1986). On the other hand, the HPRS-103 strain of Subgroup J, ALV, differs from viruses of Subgroups A to E by nucleotide changes occurring throughout the SU of its env gene (Bai et al., 1995b). However, envelope heterogeneity between Subgroup J isolates does appear to be clustered in the variable and host range regions described above (K. Venugopal, L. M. Smith, K. Howes and L. N. Payne, unpublished data). Elucidation of the host genetic control of cell receptors for ALV of Subgroups A to E coincided generally with discovery of the virus subgroups (reviewed by Crittenden, 1975; Payne, 1985). One stimulus for such work was the possibility of controlling ALV infection commercially by selection of genetically resistant stock. Three autosomal loci, tva, tvb, and tvc, with dominant susceptibility genes and recessive resistance genes, independently control susceptibility to Subgroup A, Subgroups B and D, and Subgroup C, respectively. There is disagreement about whether Subgroup E susceptibility is controlled by the same locus (tvb) that controls response to B and D, or by another locus, tve. Susceptibility of cells to infection by Subgroup E ALV is made more complex in some instances by blocking of the virus receptor by endogenous viral envelope. Genetic resistance in chickens to infection by Subgroup J ALV has not been recognized: all chicken strains are susceptible. In recent years, progress has been made in identifying the nature of the receptors to ALV. The receptor for Subgroup A is related to the low density lipoprotein receptor (Bates et al., 1993) and that for Subgroups B and D is a member of the tumor necrosis factor family (Brojatsch et al., 1996).
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of value. More specifically, the presence of ev2 or ev3 has been reported to protect birds from a non-neoplastic syndrome caused by infection with Subgroup A ALV (Crittenden et al., 1982, 1984). However, in certain circumstances they can be detrimental. Thus embryonic infection with RAV-0 causes a more persistent viremia and more neoplasms following infection with exogenous ALV, apparently due to depression of humoral immunity (Crittenden et al., 1987). Similarly, expression of EV21 ALV by the ev21 locus, which is linked with the sex-linked slow-feathering gene, K, on the Z chromosome, has a tolerizing effect on response to exogenous ALV, and has been associated with an increased incidence of lymphoid leukosis in the field and experimentally.
Although infection with exogenous ALV is widely prevalent in commercial flocks, mortality from the leukoses and other tumors is usually low, of the order of 1 to 2%. However, the significance of exogenous ALV infection began to be reassessed some 20 yr ago, following the discovery that non-neoplastic effects of subclinical infection could result in significant economic losses from suboptimal performance (reviewed by Gavora, 1987). Traits influenced unfavorably included age at sexual maturity, egg production, egg weight, fertility, hatchability, nonspecific mortality, and body weight. Such effects are of practical and theoretical importance to poultry geneticists and breeders because of the confounding effect on genetic traits. The economic losses and the effect on breeding stimulated renewed interest in control of ALV infections. Endogenous viruses can also affect production traits, by their interaction with exogenous ALV, and also directly if the endogenous virus is expressed in an infectious form (Gavora et al., 1991).
Epidemiology and Control of ALV Horizontal spread of exogenous ALV from bird to bird by contact normally leads to an immune response characterized by the development of virus-neutralizing antibodies (Payne, 1987). Sources of virus from infected birds are feces, saliva, and skin. Some birds infected in this way may become occasional shedders of ALV in their eggs and consequently transmitters of ALV to their progeny. In contrast, birds that are congenitally infected become immunologically tolerant to the virus, do not develop neutralizing antibodies, and have a persistent viremia. Hens so infected are persistent shedders of ALV in their eggs and transmitters of ALV to their progeny (Spencer et al., 1977). Infected cocks are generally considered not to transmit ALV to their progeny. Meconium from day-old congenitally infected chicks contains high concentrations of ALV and is an important source of virus for infecting hatch mates. Congenitally infected birds are more likely to develop neoplasia than birds infected by contact.
PATHOGENESIS OF REV-INDUCED DISEASES Reticuloendotheliosis virus is more closely related to mammalian retroviruses than to ALSV. The REV strains
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Influence of ALV on Production Traits
No vaccines have been developed for the control of ALV infection. Selection for genetic resistance to infection has been used by poultry breeding companies as a control measure but currently breeders mostly use schemes to eradicate ALV from their stock (Spencer, 1984). These schemes stem mainly from the work of Spencer et al. (1977), and are aimed at preventing vertical transmission of ALV from one generation to the next, and prevention of reinfection. The method uses the fact that hens that transmit ALV to their progeny can be identified by detecting ALV group-specific (gs) antigen in vaginal swabs or in their egg albumen, using an ELISA test, available commercially. Schemes for ALV eradication, for both egg-type and meat-type poultry, are applied by breeders primarily at the elite pure line level. Depending on the desired intensity of the eradication effort, the overall eradication scheme can involve a combination of a variety of procedures: 1) The essential procedure involves selection of fertile eggs for producing the next generation from hens negative for ALV shedding in tests on egg albumen and vaginal swabs, using the ELISA for gs antigen. Swab tests are usually applied a few weeks before birds come into lay; egg albumen tests are usually applied on the first eggs (often two) laid by the hen, and again when elite replacements are taken. 2) Hens may be tested for viremia just before coming into lay, discarding positive birds. 3) Chicks are hatched in isolation in small groups in wirefloored cages, avoiding manual sexing and vaccination of different pedigree groups with a common vaccination needle, to prevent mechanical spread of any residual infection. 4) The meconium of newly hatched chicks is tested for gs antigen, discarding positive dam groups. 5) ALV-free groups are reared in isolation. 6) Cocks are selected for freedom from ALV by testing cloacal swabs or semen for gs antigen. By use of such schemes in both egg and meat stock, breeders have been able to markedly reduce the prevalence of ALV infection in a few generations of testing (Okazaki et al., 1979; 1982; Payne and Howes, 1991). Complete eradication is more difficult and requires very extensive testing programs. There is evidence that congenital transmission of ALV can occur in the absence of detectable shedding of gs antigen (Ignjatovic, 1990). Use of PCR-based tests may prove of value here. Eradication from some lines has been found to be more difficult than from others. The presence of the ev21 locus slows eradication, apparently by making chicks more susceptible to posthatching ALV infection leading to viremic infections. The propensity of meat-type chicks to develop viremic infections after posthatching infection with Subgroup J ALV may also hinder eradication.
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can cause a variety of non-neoplastic lesions in chickens and ducks, collectively designated as the runting disease syndrome, two types of chronic lymphomatous disease in chickens and other poultry, and an acute reticulum cell neoplasm (reticuloendotheliosis) (reviewed by Bagust, 1993; McDougall, 1993; Witter, 1997).
Nondefective REV
Replication-Defective Strain T REV Strain T REV was isolated in 1958 from a turkey with gross leukotic lesions. Strain T has genetic deletions in the gag, pol, and env regions, and a substitution in the env region identified as the transforming gene, v-rel, most probably derived from the cellular oncogene c-rel present in normal turkey cells, and requires a nondefective REV as a helper virus to allow it to replicate. Strain T REV differs from other REV by being, like acutely transforming ALV, rapidly and highly oncogenic in chickens in vivo and in vitro. Strain T virus causes death of infected chicks in 1 to 3 wk from widespread proliferation of primitive mesenchymal or reticuloendothelial cells; there is probably more than one type of target cell, including both immature B cells and T cells. The so-called acute reticulum cell neoplasm (reticuloendotheliosis) induced is an experimental disease of chickens, and has no recognized naturally occurring counterpart.
Epidemiology and Control Serological evidence of REV infection is detected in a significant proportion of commercial layer, broiler, and turkey flocks in the U.S., usually with no disease or
deleterious effect on performance. Occasionally, however, naturally occurring lymphomatous disease associated with REV has been observed in turkeys, chickens, and other species. The REV is transmitted both horizontally by contact with infected chickens and turkeys and vertically from tolerantly infected chicken and turkey dams. Vertical transmission can also occur from infected male chickens and turkeys. There is no evidence for genetic transmission of REV. Because of the usually sporadic and subclinical nature of REV infections, no control procedures have been necessary commercially; however, it is probable that eradication could be achieved by prevention of vertical transmission through testing egg albumen samples for REV gs antigen, testing males, and rearing progeny in isolation. An intriguing recent finding has been evidence for the presence of REV genetic sequences integrated on occasions into Marek’s disease virus genome (reviewed by Isfort et al., 1994). This finding raises the possibility that the pathogenicity of Marek’s disease virus could be modified, and also that REV (and perhaps other retrovirus genomes) could be transmitted within the Marek’s disease virus genome. The prevalence of such occurrences, and their biological significance, remains to be determined.
PATHOGENESIS OF LPDV-RELATED DISEASE Lymphoproliferative disease of turkeys was first described in 1974 in the U.K. and 2 yr later in Israel (reviewed by McDougall, 1993; Biggs, 1997). Studies on the virus have been handicapped by lack of an in vitro culture system and virus characterization has depended on virus prepared from tissues of infected turkeys. An evolutionary relationship between the pol genes of LPDV and ALSV has been suggested, but apart from that LPDV has been considered to be unrelated to ALSV and REV. Sequences specific to LPDV are not present in normal turkey cells, indicating that the virus is not endogenous in turkeys. The natural disease occurs in turkeys between 7 and 18 wk of age, characterized by enlarged spleen and liver and widespread infiltration of tissues by lymphocytes, lymphoblasts, plasma cells, and reticulum cells. Experimentally, lymphoproliferative lesions are first seen in the spleen and thymus 14 d after infection of 4-wk-old turkeys. The incidence of the disease is higher in poults infected at 4 wk than at 1 d of age and is characterized by an unusual persistent viremia, immunosuppression, and hypergammaglobulinemia. The nature of this lymphoproliferative disease remains to be determined. LPDV can spread by contact, but otherwise little is known about the epidemiology of the disease. Control has been by elimination of infected turkey strains.
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Like ALV, nondefective REV are simple retroviruses with gag, pol, and env genes. They fall into a single serotype, with three antigenic subtypes. In chickens, REV can, experimentally, cause a lymphomatous disease with a long latent period that is pathologically very similar to lymphoid leukosis caused by slowly transforming ALV. The REV-induced tumor originates in the cloacal bursa, with transformation of IgM-bearing B cells, and later spreads to the liver and other organs. Lymphoma induction is associated with integration of REV proviral genome adjacent to the c-myc gene. A second type of chronic lymphoma in chickens occurs experimentally more rapidly, by 6 wk. The second type is a T cell neoplasm, again associated with activation of cmyc by insertional mutagenesis, and involves the thymus, liver, spleen, heart, and peripheral nerves, but not the cloacal bursa. In turkeys, REV causes a lymphomatous disease, naturally and experimentally; chronic lymphomas caused by REV have also been described in ducks, geese, pheasants, and quail. The nature and molecular basis for these lymphomas in species other than chickens are not well understood.
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CONCLUSIONS
REFERENCES Bacon, L. D., R. L. Witter, and A. M. Fadly, 1989. Augmentation of retrovirus-induced lymphoid leukosis by Marek’s
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Infections by avian retroviruses show features that set them apart from other avian virus diseases. Central is the occurrence of vertical transmission, which maintains the infection from one generation to the next, and which provides a source of early contact exposure of uninfected chicks. In consequence, vaccination has not been seen as a preventive measure, and in fact in limited studies candidate vaccines have not been effective. Over the past century, control has been by adoption of principles of good husbandry (to reduce contact spread), genetic selection against tumor incidence or virus infection, and most recently by schemes for eradicating the infections from breeding stock. This last provides the ideal approach, but it is demanding in resources and technology. For the most part, these measures have controlled infection and disease adequately. Nevertheless, retroviruses remain a constant and unpredictable threat, as recent outbreaks of hemangiosarcomas in Israel, and currently myelocytomatosis in several countries, remind us. In the latter instance, a new virus, which appears to be a recombinant involving endogenous viral sequences, is responsible, highlighting the need to understand relationships between exogenous and the ubiquitous endogenous viruses. Furthermore, new practices introduced by the poultry industry may lead to unexpected problems, as exemplified by the occurrence in the field of enhancement of lymphoid leukosis losses by the endogenous EV21 virus, associated with the slow-feathering gene, and of the same disease by use of certain Marek’s disease vaccines. Subsequent elegant research has not only contributed to an understanding of the scientific basis of these phenomena, but has revealed significant new scientific principles. A lesson is that it is likely that there are other unrecognized factors in the field that influence tumor incidence that need to be identified and understood. Within the past 20 yr or so the era of molecular biology has been entered, the powerful techniques of which have touched every aspect of the study of avian retroviruses. Much of the work done has come from biomedical laboratories in which these viruses and diseases are studied as models of viral oncogenesis; the discovery of oncogenes coming from such work has justified this approach. An exciting historical account of this recent work is provided by Weinberg (1997). However, knowledge so gained has also been applied beneficially to problems more related to the poultry industry. Even so, the flow of knowledge has not been entirely one-way. What can be expected is that this knowledge will lead to new ways of controlling retroviruses and the associated neoplastic diseases. Ellermann and Bang (1908), and Rous (1910), the originators of avian tumor virus research, would be satisfied with the progress being made.
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