Human T-cell leukemia viruses: epidemiology, biology, and pathogenesis

Blood

Revie1v.s (1997)

G 1997 Pearson

11~ 9 1-l 04 Professional Ltd

Transfusion-transmitted

infections

Human T-cell leukemia viruses: epidemiology, biology, and pathogenesis

0. C. Ferreira Jr, V. Planelles, J. D. Rosenblatt The human T-cell lymphotropic viruses type I and type II are closely related human retroviruses that have similar biological properties, genetic organization and tropism for T lymphocytes. Along with the simian T-cell lymphoma virus type I, they define the group of retroviruses known as the primate T-cell leukemia/lymphoma viruses. Initially identified in 1980,the human T-cell lymphotropic virus type I has been implicated as the etiologic agent of adult T-cell leukemia/lymphoma and of a degenerativeneurologic disorder known as tropical spastic paraparesisor human T-cell lymphotropic virus type I-associated myelopathy. The intriguing link between human T-cell lymphotropic virus type, T-cell malignancy, and a totally unrelated and non-overlapping neurological disorder suggests divergent and unique pathogenetic mechanisms. This review will addressthe epidemiology, molecular biology, and pathogenesisof human T-cell leukemia viruses.

EPIDEMIOLOGY

Southeastern United States,’ Melanesia8 and parts of South America’) HTLV-I has also been found to be prevalent in certain population groups in the Middle East”’ and India.”

Human T-cell lymphotropic virus type I distribution Human T-cell lymphotropic virus type I (HTLV-I) was first identified in 1980’,’ and most of what we know about its distribution in the world is due to the recognition of the unusual diseases associated with HTLV-I such as adult T-cell leukemia/lymphoma (ATL) and/or HTLV-associated neurologic disease. Extensive seroepidemiological studies have often followed the report of an HTLV-I-associated disease in a given region. Although HTLV-I infection has been reported in virtually every region of the world, moderate-to-high rates of infection can be found in Southern Japan,’ the Caribbean basin,” Central and West Africa,‘h the

Human T-cell lymphotropic virus type II distribution The geographic ‘origins’ of HTLV-II are not known. HTLV-II has been reported mainly in intravenous drug users (IVDUs), their sexual contacts and certain Amerindian populations. HTLV-II is endemic in IVDUs in the USA,‘” Europe]’ (Italy, Spain, France. Norway, Sweden and the UK), South America (Brazil),‘” and Southeast Asia (Vietnam).” HTLV-II has generally been more frequently identified than HTLV-I in IVDUs. studies have In the past, seroepidemiological defined endemic foci of HTLV-II among Amerindians. It is interesting to note that culturally and ethnically distinct Indian groups, geographically distributed in North America (New Mexico and Florida

Correspondence to: Joseph D. Rosenhlatt MD, Professor of Oncology in Medicine, Microbiology and Immunology; Unit Chief, Hematology-Oncology, University of Rochester Medical Center, 601 Elmwood Avenue. Box 704, Rochester NY 14642. USA.

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in the USA),j6 Central America (Panama),” and South America (Argentina, Brazil, Colombia, and Chile)18 ” are infected with HTLV-II. Based on this pattern of HTLV-II distribution in the Americas, it was originally thought that HTLV-II may have originated in the New World. However, the recent finding of HTLV-II infection among pygmies in Africa, where HTLV-II is otherwise rare, conflicts with this hypothesis2 The evolutionary relationship of HTLV-I to HTLV-II is not well understood, despite the extensive similarity in sequence and genomic organization, and both viruses are thought to derive from a common precursor. Transmission In most individuals, HTLV-I and HTLV-II are associated with lifelong asymptomatic infection. These viruses are transmitted at birth by infected mothers or later in life through sexual contact, by blood transfusion, and by needle sharing among IVDUs. In contrast to the mode of perinatal transmission for human immunodeficiency viruses type 1 and type 2 (HIV), mother-to-child transmission of HTLV-I and HTLVII occurs primarily by breastfeeding through ingestion of infected milk-borne lymphocytes.23 The transmission efficiency is dependent on the duration of breastfeeding, the presence of maternal antibodies to HTLV-I, and has been estimated at up to 20%.24.‘5The time of infant seroconversion typically ranges from 1 to 3 years of age.25,2h Sexual transmission of HTLV-I is bi-directional.” However, the frequency of HTLV-I transmission is much higher from male to female than the reverse.27m2” For instance, after 10 years of sexual contact with an infected partner, a woman has a 60% likelihood of being infected, as opposed to only 0.4% for a man. The presence of genital ulcers increases the risk of virus transmission.” Other risk factors correlated with HTLV-I/II sexual transmission include high viral load and high titers of anti-HTLV antibodies.28,29 Transfusion with cellular blood components, but not with plasma, is the most efficient route of HTLV1 transmission, with a seroconversion rate of approximately 50%.30~3’Storage of a blood unit for more than six days markedly decreases the likelihood of transmission3* HTLV-I transmission by blood products can lead to rapid development of HTLV-Iassociated myetopathy (HAM) or tropical spastic paraparesis (TSP), and has been seen within six months of transmission.33 Concern about HTLV-I transmission through blood transfusion has led to the introduction of routine blood-donor screening for antibodies to HTLV-I in the USA and other countries.

Diagnosis Discrimination between HTLV-I and HTLV-II infection is difficult because of the high degree of amino acid homology between the two viruses.‘J The most commonly used screening test for HTLV is an enzyme-linked immunosorbent assay (ELISA).” Currently licensed anti-HTLV-I ELISA kits use inactivated HTLV-I whole virus lysate as antigen, which appears to detect most HTLV-II-infected individuals as we11.36 After initial reactivity on ELISA, a supplemental test is necessary to confirm true HTLV-I/II antibody reactivity. Western blot is the usual confirmatory assay, but other assays such as immunofluorescence, radioimmunoprecipitation (RIPA) line immunoassay (LIA), or polymerase chain reaction (PCR) have also been used.35m17 Because most supplemental serological assays cannot discriminate between HTLV-I and HTLV-II infection, PCR has been used to identify type-specific proviral sequences in peripheral blood mononuclear cells.” In addition to PCR, immunological reactivity to recombinant proteins and synthetic peptides derived from HTLV-I and -11 has also been used to discriminate HTLV-I from HTLV-II.j8

GENETIC

VARIABILITY

Human T-cell Iymphotropic virus type I In contrast to HIV-I, where considerable genomic variability is seen between isolates, different HTLV-I isolates show a high degree of sequence conservation? 43The overall nucleotide divergence of HTLV-I strains from Japan, Africa, the Caribbean basin, and the Americas is approximately 4%, depending on the region of the genome analyzed.39A2 Recently, a somewhat more divergent variant of HTLV-I was discovered in Melanesia, but even this HTLV-I strain is 92% homologous to all other known HTLV-I isolates.“” Variation in nucleotide sequences in some regions of the HTLV-I genome has been correlated to the geographical origin of the virus.43 According to this genetic analysis, three subtypes or ‘clades’ of HTLV-I are known”? (1) the ‘cosmopolitan’ HTLV-I, which includes isolates from Japan, Caribbean, Africa, North and South America; (2) the Zairian subtype; and (3) the Melanesian HTLV-I (HTLV-IMe,), the most divergent subtype. Some investigators have further divided the cosmopolitan sub-type into a West African, Japanese, and ‘true’ cosmopolitan clade. The majority of nucleotide differences between isolates are single-point mutations and no clustering of disease-specific sequences has been found for HTLV-I strains isolated from HTLV-I carriers or patients with ATL or TSP/HAM.J3 As opposed to HIV-I, specific

Human

cellular tropisms or pathogenic correlations among isolates of divergent sequence have not been observed. Thus, the genomic variability of HTLV-I appears to reflect the geographic origin and/or the migration of ancient populations carrying the virus, and does not correlate with the viral phenotype or clinical outcome. Genetic variability studies also helped to establish the evolutionary relationship between the so-called primate T-cell lymphotropic viruses (PTLV).” The PTLV group contains HTLV-I, HTLV-II and two simian T-cell lymphotropic viruses (STLVs) isolated from Asian and African non-human primates. HTLVII is the most different in sequence among the PTLV and appears to have diverged first. The Asian STLV diverged next, followed by the HTLV-IMc,. African STLV is thought to have segregated from HTLV-I more recently.” Human T-cell lymphotropic virus type II Initial studies comparing genomic sequences of HTLV-II isolates have clearly demonstrated the existence of two HTLV-II subtypes: HTLV-IIa (formerly known as HTLV-II MO) and HTLV-IIb (formerly designated HTLV-II NRA).“’ This subtype discrimination is based on relative divergence of nucleotide sequences of the envelope (4.3%) gug (3.8’%), and long terminal repeat (LTR) (5.7%) regions.“” The predicted amino acid sequence of the HTLV-IIa and HTLV-IIb Turx protein suggested a possible functional difference between the Tax proteins of these virus subtypes.” A two-nucleotide substitution near the 3’ end of the HTLV-IIb Tu.u coding sequences results in an Arg residue instead of the stop codon present in the HTLV-IIa Tux protein, leading to an HTLV-IIb Tux protein that is 25 amino acids longer than the HTLV-IIa Tux protein. In transient transfection assays, HTLV-IIb Tax is a five fold more potent transactivator of the HTLV-II LTR than HTLV-Ha Tux protein.‘” In vivo consequences of this functional difference remain to be established. Molecular epidemiological studies have shown that HTLV-1Ia is the predominant infection in IVDUs in urban North America.“’ HTLV-IIb seems to be the predominant subtype in Indian groups in Panama, Colombia and Argentina.“’ Although HTLV-IIb infection predominates in North American Indian groups, some individuals have been infected with both subtypes.“) Recently, the existence of a third molecular subtype of HTLV-II ~ HTLV-IIc ~~in urban Brazilian and Indian populations has been demonstrated.‘” HTLVIIc has LTR and em nucleotide sequences more closely related to HTLV-IIa, but a nucleotide and a predicted amino acid sequence for tax similar to that

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of HTLV-IIhJ8 Functional analysis of the Tus protein from subtypes IIa, IIb and IIc, demonstrate similar transactivating properties for the IIb and 11~ TU.Y proteins.”

MOLECULAR

ORGANIZATION

The proviral genome of HTLV-I and HTLV-II encodes of all known retroviruses.” Both ends of the genome are flanked by non-coding direct repeats known as long terminal repeats (LTRs). The LTRs mediate proviral integration and contain cis-acting regulatory elements important for viral transcription, viral mRNA processing and reverse transcription, In addition, there is a unique region at the 3’ end of the genome, called pX, that contains four small open reading frames (ORFs): X-I, X11, X-III, and X-IV.” The ORF X-III and X-IV encode the regulatory proteins re.x and tax, respectively. At least three different mRNA species are detected in HTLV-infected cells: the genomic or unspliced mRNA and two subgenomic, single (4.3-Kb) and doubly (2. lKb) spliced mRNA.“.i’ The HTLV I-11 genome is graphically represented in the figure. The gaglpol precursor proteins are encoded by unspliced full-length mRNA. The translated precursor protein (pr53) is cleaved by the viral protease into p19 matrix protein, p24 capsid protein and p12 nucleoprotein that binds to the genomic RNA in the mature viral particle.‘” The pal gene product is translated from the same genomic mRNA from a different frame than gllg.” A ribosomal frameshift redirects the translational machinery to read the pal gene message producing a precursor gag/pal protein.i’ This frameshift occurs with low frequency, thus more pr53 is produced than the gag/p01 precursor. The latter protein is cleaved by the protease to yield the reverse transcriptase and the integrase proteins, in addition to the previously mentioned Gag proteins.” Both pol proteins are important in the early events following infection and mediate reverse transcription of viral RNA into DNA and integration of the DNA in the human genome as a provirus. The ORF for the HTLV protease overlaps with parts of the translated 3’ sequence of the gllg and the 5’ sequence of the pol genes.” Translation of the protease is thought to be mediated by ribosomal frameshifting. The protease is important in gag precursor processing and in the later events of the viral life-cycle, where it is responsible for particle maturation, following viral budding. The single-spliced 4.3-kb mRNA encodes the precursor envelope protein (gp61). Gp61 is cleaved by an unknown cellular enzyme to yield the gp21 transmembrane protein and the gp46 Env surface protein. Gp46

gug, [WI, and enr genes characteristic

A

LTR lJ3

+ “X”

RU5

region

LTR +U3RU5

I I sw

+ 1

PO1

6

C

Fig. Molecular

features of HTLV. A. Genomic organization. Long terminal repeats (LTR) and open reading frames are depicted. Translational start (ATG) and stop codons (diamonds) are indicated. ‘X’ denotes intergenic region containing multiple short open reading frames (see ref.149). B. HTLV produces multiple RNA species by alternate splicing. Open reading frames encoded by the different RNA species are indicated. Solid lines represent exons and discontinuous lines represent introns. p12 can be expressed by singly- and doublyspliced mRNAs (Koralnik et al. J Virol 1993; 67: 2360). UP, unspliced; SP, singly-spliced; DP, doubly spliced. C. Translation of polycistronic messages by ribosomal frameshifting (FS). D. Translation of polycistronic messages by readthrough of a week’s translational ATG. For details see text.

Env interacts with a still unidentified cellular receptor to facilitate viral entry. The double-spliced 2. I-kb mRNA encodes at least two important viral regulatory proteins, tax and rex, in addition to the ~21’.“’ (Fig.). Tax is encoded by the X-IV ORF and rex by the X-III ORE In HTLV-I, tax is a 40-kD protein (~40’““) while HTLV-II tax is a 37kD nuclear phosphoprotein.54.55 Radioimmunoprecipitation with antiserum to carboxy-terminal X-III ORF coding sequences demonstrates two protein species for HTLV-I: ~27’.“’ and p21x-“1.56In HTLV-II, two proteins of molecular weight 26 kD (~26~-~) and 25 kD (~24~-~) are seen.s7 The ~21’.“’ protein of HTLV-I has the same carboxyterminal sequences as ~27’.“’ but apparently uses another AUG initiation codon located downstream of the rex initiation codon.SR So far, there is no definitive evidence for the role of ~21”.“I in the viral life-cycle, although it has been suggested that it may antagonize yex function.5’ Recently, two additional proteins of unknown function, designated ~12’ and p30”/tof, have been reported to be encoded by X-I and -11 ORF on both the single- and double-spliced mRNA for HTLV-I (Fig.).60 DNA sequences encoding ~12’ from 21 HTLV-I-positive individuals, including eight patients with HAMITSP and seven with ATL were highly conserved.‘@ The pl2’-protein encodes at at least four putative SH3 binding motifs known to be important

in protein-protein interactions.‘50 The p 12’ protein can co-operate with the E5 protein of bovine papilloma virus in transforming murine fibroblasts in vitro.‘5’ Both E5 and ~12’ localize to the cellular endomembrane, and appear to interact with a vacuolar H’ ATPase,‘5’m’53involved in proton transport into cellular organelles. The ~12’ protein also binds to the p chain of the IL-2 receptor, in a region which also binds to the ~56’“~ kinase involved in T-cell activation by IL2.‘j4 Both /3 and xc chain expression on the cell surface is downregulated by p12’, although effects on signaling still need to be characterized.“4 Additional proteins encoded by ORF II in HTLV-I (p30”, ~13”) have been described as well, but a role has not yet been assigned for these proteins in the viral life-cycle or in transformation.‘i4 It should be noted that, in the case of HTLV-II, deletion of the region between env and the 3’ tax/rex exon does not impair virus replication or T-cell transformation.‘5j Hence, the role of p 12’, p30”, p13”, in HTLV-I, or the postulated plO’, ~28” proteins in HTLV-II remains unclear. Tax: a promiscuous regulator of transcription Tax is a trans-activating phosphoprotein that regulates viral transcription by interacting with three 21bp enhancer elements located in the U3 region of the proviral LTR.h’ This region contains several DNA motifs with homology to known cellular transcrip-

Human

Table

Cellular

Oncogenes.

genes dysregulated

transcription

factors

by tax Effect

on transcription

C-SOS

; t

c-my egr- I Growth

factors.

cellular

receptors

ILZR-c( IL-I I L-7 I L-3 IL-6 c-sis (PDGF) GM-CSF TGF-P PTHrP vimentin MHC-I DNA

repair

p polymerase Revised 413197

leukemia

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9.5

ATL cells, is thought to be initiated by Tut induction of IL-2Ra expression. The humoral hypercalcemia frequently observed in ATL, even in the absence of bone lesions, may be mediated in part by PTHrP, a paraneoplastic fetal hypercalcemic factor known to be induced by HTLV-I/II tux (for review see”‘). Similarly, fcr.vinduction of early response genes, such as c>gr-1and/or c-j&s may play a role in T-cell transformation by the virus (reviewed in”’ ““). Finally. soluble tus may be released by HTLV-I infected cells. leading to secondary proliferation of non-infected cells and/or transactivation of cellular genes in ‘bystander’ cells.‘“’ Ihi Hence, tar may play an important role in neoplastic transformation as well as in virus replication. Rex: a post-transcriptional

enzymes

T-cell

regulator of viral gene

expression 1

tional factor binding motifs, such as the cyclic-AMPresponsive element (CRE), nuclear factor KB (NF-KB) and serum responsive element (SRE). Tux does not bind directly to DNA but rather, it appears to mediate its effect by activating different cellular transcription factors that in turn bind to the LTR and activate viral transcription.“’ At least two fnx-responsive elements (TRE- 1, TRE-2) are located within the U3 portion of the viral LTR. TRE-1 contains binding motifs for members of the cyclic AMP responsive element binding family of transcription factors (CREB/ATF) (for review, see’4”.‘5h.‘“‘),while TRE-2 binds a variety of transcription factors such as ets-I and Spl, and Myb.‘5” “” Tax may bind directly to CREB and the related cyclic AMP responsive element modulatory (CREM) proteins, and increases activity of these factors.‘” Once activated, these transcription factors can also bind to and induce transcription from many other cellular genes (Table). Many cellular gene promoters that are responsive to tus transactivation have been identified, including the IL-2R a-chain, parathyroid hormone-related protein, (PTHrP), GM-CSF, B-globin, c-j&, egr-1, MHC class I, c&s, vimentin, IL-l, IL-2, IL-3, IL-6, NFKB, and TNF-B (for review see “,“‘)). Tm has also a reported repressive effect on expression of the DNA repair enzyme P-polymerase (Table).h’ Many of these effects are thought to play a role in conferring the transformed phenotype of HTLV-I/II infected T-cells and possibly a role in pathogenesis. For example, the vigorous induction of expression of the high-affinity IL-2 receptor in HTLV-I/II transformed T-cells, and

In complex retroviruses such as HTLV-I/II and HIV-I, there is a need to carefully regulate viral mRNA transcription, as well as mRNA processing. The WY proteins of HTLV-I/II play an important role in regulating viral mRNA processing. Proviruses with mutations in rr.v fail to export full length gag/p& mRNA from nucleus to cytoplasm, despite adequate levels of viral mRNA production. Rex appears to be necessary for export of full-length gug/pol and single-spliced clzi mRNA from nucleus to cytoplasm.‘h.h’ This function is analogous to that performed by Rev in HIV-I/II and Rex can functionally replace the HIV-I Rev protein.lh” i(rhRex localizes to the nucleus, and specifically to the nucleoli of infected cells.‘h”h’ RPX appears to be phosphorylated on a serine residue, and phosphorylated rex binds with high affinity to &acting RNA sequences, called the WY responsive element (RxRE) in the viral mRNA.““.“” 17’ This interaction appears to facilitate exit of mRNA from nucleus to cytoplasm. Recent experiments using HTLV-II WY suggest that wx binding may also inhibit mRNA splicing, by preventing early steps in spliceosome assembly.h7In addition, a suppressive effect of nuclear transport conferred by the &-acting repressive sequences (CRS) is apparently relieved upon rrs binding to the RxRE.“’ As a consequence of wx accumulation in the cell, there is an accumulation of unspliced and single-spliced mRNA, favoring the production of the viral structural (gag) and env proteins. This is also accompanied by a decrease in the levels of double-spliced mRNA encoding tax and WY. Recent experiments with HTLV-II W.Y also suggest that KY accumulation may also inhibit ttrx-mediated transcription, in effect slowing viral transcriptionh Therefore, the fine balance between tu.Yand WY expression and function may ultimately dictate the state of viral replication within infected cells.

CLINICAL

SYNDROMES

Adult T-cell leukemia/lymphoma Adult T-cell leukemia/lymphoma (ATL) was initially described in Japan in 1977 by Takatsuki.“’ It was noted that a particular type of T-cell leukemia was associated with the presence of lymphocytes with multilobulated nuclei, frequent bone lesions, hypercalcemia, rapid progression to death, and that cases clustered in a geographical region in Southern Japan. This disease, called ATL, is characterized by a malignant proliferation of a mature T lymphocyte with a phenotype of CD2+, CD3+, CD4+, CD8, and HLA-DR’. Typically, cells with lobulated nucleii known as ‘flower’ cells are seen.7” In addition, ATL cells are characterized by high levels of expression of the IL-2 receptor a-chain, the CD25 antigen.” The leukemic cells are clonal, as demonstrated by monoclonal integration of HTLV-I provirus, although the site of integration varies between individual patients.“” The lifetime risk among HTLV-I carriers for development of ATL has been estimated at 1 to 4%.‘* The time between infection and actual development of disease has been estimated to be 30-50 years.72,7’This is based on the fact that in most, if not all cases of ATL, HTLV-I infection was acquired at birth and to the fact that the disease develops at adulthood, usually after 40-50 years of age. Cases of transfusion-associated ATL are rarely seen. Clinically, there are several subtypes of ATL: acute, chronic, and smoldering.74 Acute ATL is characterized by a high white-blood-cell count, which is accompanied by the presence of ‘flower’ cells, peripheral adenopathy, and hepatosplenomegaly. Acute ATL may present as a leukemia or as a high-grade nonHodgkin’s lymphoma with frequent involvement of the peripheral blood. Frequently, hypercalcemia, skin lesions, lytic bone lesions of the skull and long bones, and pulmonary involvement are also seen. Opportunistic infections such as Pneumocystis carinii and cytomegalovirus are common in late stages of ATL. Despite intense chemotherapy, over half of the patients die before 6 months. The lymphomatous form of ATL is characterized by tissue localization, in particular in lymph nodes, and the absence of large numbers of circulating malignant cells. The diagnosis is suggested by the presence of cells with a multilobulated nuclei and with a CD4+, HLA-DR’ and CD25’ surface phenotype. The median survival time for these patients is short (10 months), as in ATL.7J The smoldering form is characterized by relatively few circulating leukemic cells, the presence of skin lesions and occasionally by pulmonary invo1vement.74 This phase is often indolent, and can last for years.

Chronic ATL is accompanied by an increased number of circulating leukemic cells and increased infiltration of the skin, liver, spleen, and lung. Transition to acute form from both smoldering and chronic phases can occur at any time during the disease course. Median survival for the chronic subtype is 24 months and may be even longer for the smoldering subtype.74 The histopathology of ATL is highly variable but frequently ATL resembles a diffuse large cell lymphoma.75 Histopathologic ‘grade’ does not appear to have prognostic significance for the various subtypes of ATL.‘j Recently, the presence of deleted HTLV-I provirus was noted in T cells derived from several patients with mycosis fungoides and Sezary syndrome.q’.9’ In a subgroup of patients with otherwise classical cutaneous T-cell lymphoma, expression of taxlrex mRNA was detected in the PBMC.9’ Pancake and ZuckerFranklin have reported the presence of antibody against HTLV-I tax in patients with mycosis fungoides who were seronegative for HTLV-I structural proteins.94 These provocative findings still need to be verified before mycosis fungoides can be convincingly linked to ‘seronegative’ HTLV-I infection. HTLV-I-associated paraparesis

myelopathyltropical

spastic

HAM/TSP is a chronic, progressive demyelinating disease that predominantly affects the spinal cord. This disease is reported to affect between 0.2 and 5% of infected individuals.76 The disease is more frequent in women than in men (female to male ratio of 2:l). Typical onset of HAM/TSP is in the fourth decade of life.” However, transfusion of HTLV-I-infected blood can result in development of HAM/TSP within as little as 6 months.” The most prevalent initial symptoms of HAM/TSP are weakness and stiffness of the lower limbs.77,78Other common presenting symptoms are lumbar pain, a variable degree of sensory loss, and bladder disturbances such as urinary urgency and incontinence. As the disease progresses, constipation, ‘megacolon’, impotence, pain during penile erection, and decreased libido may become apparent. Hyper-reflexia of the lower limbs and Babinski reflex are often seen early in the course of HAM/TSP. Small numbers of atypical lymphocytes resembling ATL ‘flower’ cells are seen both in the peripheral blood and cerebral spinal fluid (CSF) of patients with HAM/TSP.‘* Immunoglobulin and protein levels are moderately increased in the CSF, and oligoclonal immunoglobulin is frequently seen in the CSF.“.” The disease frequently progresses more rapidly over a 5-IO-year period and then tends to stabilize with severe levels of chronic disability.‘9

Human

Autopsy and pathologic studies have shown a perivascular and parenchymal infiltration of mononuclear lymphoid cells accompanied by myelin and axonal destruction.x”,x’ This process results in a severe degeneration of the white matter most conspicuous in the thoracic spinal cord.“‘” Other diseases associated with HTLV-I

HTLV-I has been implicated as an etiologic agent for other diseases, including some cases of polymyositis,“’ polyarthritis,*’ and uveitis.“J.8’ Infectious dermatitis in children,“’ and virulent strongyloidiasis8” has been described in HTLV-I carriers and in patients with HAMITSP, generally in endemic areas such as Japan and Caribbean basin. HTLV-I proviral DNA has been detected in lymphocytes isolated from the anterior chamber in patients with HTLV-I associated uveitis, but not from two HTLV-I positive patients with uveitis of other welldefined causes.” Additionally, viral mRNA was detected in T-cell clones derived from the aqueous humor of patients with HTLV-I uveitis.X7.XX These data have led to speculation that HTLV-I may be directly implicated in ocular inflammation in patients with uveitis.X’.XX HTLV-I has also been linked to pathogenesis of a form of arthritis in infected patients, known as HTLV-I-associated arthropathy.‘3xy Arthritis has been described in patients with HAM/TSP and a sub-group of patients with chronic inflammatory arthropathy have also been shown to be seropositive for HTLV-I.“’ Oligoclonal proliferation of HTLV-I infected T cells has been observed in the synovial fluid of patients with HTLV-I associated arthropathy8’ and HTLV-I viral ta.drex mRNA has been detected in fresh synovial tissue.“’ Transgenic mice carrying the HTLV-I tux gene develop a chronic inflammatory arthropathy,“’ which may be a model for pathogenesis of this disorder.

HTLV-II

ASSOCIATED

DISEASES

HTLV-II was initially isolated from a T-cell line (MO-T) derived from a patient with a rare variant form of hairy cell leukemia.” A second patient with a CDS+ T-cell leukemia and coexistent B-cell hairy cell leukemia was noted to be infected with HTLV-II.” However, an association between hairy-cell leukemia and HTLV-II infection has not been confirmed.” Recently, HTLV-II sequences have been found in the mononuclear leukocytes of some patients with mycosis fungoides by the same group that reported HTLV-I sequences in these patients”’ and in rare patients with large granular lymphocytic leukemia. ‘)’ Therefore, HTLV-II appears to have a role in rare T-cell lymphoproliferative disorders.

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In vitro, HTLV-II is tropic for CD8’ T-cells,” and it is noteworthy that several of the casesof HTLV-II-associated leukemia have been of the CD8’ T-cell lineage.‘“““.4” HTLV-II has also been detected in a small number of patients with a spastic myelopathy and variable degrees of ataxia.“‘“,“” In addition, a neurological syndrome similar to HAM/TSP has been described in rare patients co-infected with HIV-l and HTLV-II.““ Finally, at least one HTLV-II infected patient has been identified with a chronic progressive neurological disease clinically indistinguishable from HAM/TSP.‘“’ In the latter patient, no other known human retrovirus could be detected, suggesting that both HTLV-I and HTLV-II may be linked to HAM/T% PATHOGENESIS Adult T-cell leukemiallymphoma

The first important observation regarding pathogenesis of malignancy by HTLV-I was the absence of any viral oncogenes derived from cellular proto-oncogenes in the HTLV-I genome.” Furthermore, activation of cellular oncogenes by preferential HTLV-I integration has not been reported.“” Rather, HTLV-I integration in ATL appears to be random, although the site(s) of integration in a given leukemic patient are identical for all leukemia cells, indicating that ATL generally arises from a single virally infected clone.“‘4 T-lymphocytes isolated from the peripheral blood of HTLV-I infected individuals show increased spontaneous proliferation (SP) in vitro.“” With time, this proliferation becomes independent of IL-2 stimulation. Freshly isolated T cells from carriers also may display the phenotypic characteristics of activated lymphocytes with high expression levels of IL-2R achain, HLA-DR and ICAM-1.“‘““” These observations suggest involvement of viral protein(s) in the proliferation and the activation phenotype of the HTLV-I-infected T lymphocyte. Several lines of evidence suggest that the viral transactivator protein Tax mediates the transcriptional activation of many cellular genes involved in cytokine production, response. and cell proliferation (for review, see”‘). In particular, the IL-2R a-chain is constitutively expressed in all HTLV-I-infected cells. The promoter region of the IL-2R a-gene contains a binding motif for NF-lcB.“‘* Transactivation by Tax is mediated through the NF-K-B motif.“‘” NF-K-B is usually retained in the cytoplasm by the interaction with the IKB molecule. Tax can apparently disrupt this association and allow NF-KB to migrate to the nucleus”‘” leading to transactivation of the IL2Ra promoter and constitutive expression of the highaffinity interleukin-2 receptor. Deregulation of T-cell

proliferation by HTLV-I through effects on IL-2Ra expression and NF-KB has therefore been implicated in leukemogenesis. In the past few years, the mechanism of cell signaling by the IL-2/IL-2R system has been dissected in detail.“” The IL-2R is a protein complex composed of IL-2Ra, IL-2RB and IL-2Ry, chains. IL-2 binding induces heterodimerization of B and y chains that are required for IL-2 signaling. This heterodimerization leads to phosphorylation of the Janus kinases, Jakl and Jak3 on tyrosine residues, which in turn phosphorylate a group of transcription factors known as STATS (for signal transduction and activation of transcription).““.“, Once activated, STAT proteins translocate from the cytoplasm to the nucleus, where they function as transcriptional activators. Constitutive high-level expression of IL-2R a-chain in HTLV-I infected cells suggested the possibility that in ATL cells the IL-2R mediated signal might be triggered independently of IL-2 binding. Constitutive phosphorylation of the Jak3 protein has been described in some HTLV-I transformed, IL-2 independent, cell lines.“’ Furthermore, constitutive activation of Jak3 correlated with acquisition of IL-2 independence in an HTLV-I infected cord blood lymphocyte line.‘13 However, we have observed several IL-2 independent HTLV-I transformed T-cell lines in which constitutive JaWSTAT activation is not observed (Ferreira, unpublished observation). Finally, it has been proposed that transactivation of protooncogenes such as c-fos, egr-1 and egr-2 by Tax may further contribute to leukemogenesis (for review, see62). The interaction between HTLV-I proteins with components of the IL-2R system may be even more complex. The HTLV-I ~12’ protein was recently found to downregulate surface expression of both B and 7, chains of the IL-2R.“” Since ~12’ appears to bind to both p and y, chains, ‘I4 it might also potentiate p and r, chain heterodimerization, and potentially trigger IL2R signaling. The role of viral proteins may be restricted to an early stage of HTLV-I infection. Since tax mRNA and/or protein is not detectable in most circulating ATL cells, tax-independent mechanisms have also been invoked.“’ Tax and possibly ~12’ likely play a role in early leukemogenesis by expanding the pool of proliferating T cells and thereby creating the conditions for subsequent genetic events that lead to frank T cell malignancy. Tax has been observed to transcriptionally repress the B-polymerase gene involved in DNA repair, suggesting that genetic instability may be an additional consequence of HTLV infection.63 The frequent finding of chromosomal translocations particularly involving chromosome 14 in patients with ATL lends additional support to the notion of increased genetic instability.“h Other studies have

demonstrated frequent structural abnormalities in chromosome 6 associated with an aggressive clinical course.“’ Mutations of the p53 tumor suppressor gene have also been found in a subset of patients with ATL.“’ Of note, HTLV-I/II infected T cells have also been noted to secrete chemokines such as RANTES (regulated on activation normal T-cell expressed and secreted), and MIP-la suggesting that infected cells may actually ‘recruit’ uninfected T cells which can then be infected by cell-to-cell contact, expanding the pool of HTLV-infected cells.“” It is not known whether chemokine elaboration is another consequence of transcriptional deregulation by Tax. The highly characteristic CD4’ T-cell leukemogenesis observed with HTLV-I has not, however, been linked to a specific translocation or genetic event and still defies molecular explanation. HTLV-I-associated paraparesis

myelopathyltropical

spastic

ATL represents a disease of uncontrolled replication and expansion of a single T-cell clone. In contrast, HAM/TSP is associated with oligoclonal/polyclonal activation and proliferation of T cells accompanied by a chronic inflammatory process affecting the central nervous system.8’,‘20 At the cellular level, there is an intriguing difference between ATL cells and PBMCs isolated from HAM/TSP patients. Typically, expression of IL-2R achain parallels transcription of the tax gene in PBMC from HAM/TSP patients.lzO In contrast, IL-2R achain transcripts are detected in ATL cells without overt evidence of tax expression.“5 HAM/TSP patients have higher overall levels of viral load as assayed by PCR when compared with asymptomatic carriers, although the tax mRNA transcript level per infected cell is similar.“’ Two major models have been proposed to explain the chronic inflammation and CNS destruction in HAM/TSP: an autoimmune model and a cytotoxic mode1.‘23 Several lines of evidence support the cytotoxic model. First, patients with HAM/TSP of HLAA2 haplotype carry a high frequency (approximately 1:500) of circulating HLA-A2-restricted CD8’ cytotoxic T cells reactive to Tax.‘24,‘25Second, astrocytes have been shown to express HTLV-I tax mRNA, as detected by in situ hybridization.‘2h Therefore, the appropriate localization of an immune target cell and the existence of HTLV-I tax-specific cytolytic T cells support a cytotoxic model for pathogenesis. Since cell-free transmission HTLV-I is not thought to occur, it is not clear how astrocytes are infected. Histopathological findings show a mixture of infiltrating CD4’ and CD8’ T-lymphocytes in the CNS during

Human

the early phase of HAM/TSP, followed by the predominance of CDS+ lymphocytes in the later stages of the disease.“’ Investigators have also noted infected monocytes in patients with HAM/TSP, which might serve as a vehicle to introduce HTLV-I into the CNS.“’ It is conceivable that an initial wave of infiltrating lymphocytes and/or monocytes may contain infected cells with the ability to transmit HTLV-I to astrocytes, which is then followed by infiltration of HTLV-I-specific CDS+ lymphocytes and targeting of infected cells. However, it remains to be demonstrated whether the astrocytes, other CNS cells, or the HTLVI-infected CD4’ lymphocytes, are the primary target(s) for cytolytic T-cells in HAM/T% Evidence supporting an autoimmune model is indirect. In this model, damage to the CNS is mediated by infiltration of the activated auto-reactive HTLV-Iinfected CD4’ lymphocytes.‘” First, familial clustering of some HLA haplotypes has been associated with development of HAM/TSP in Japan.“*.“’ Second, other diseases anecdotally linked to HTLV-I infection, such as Sjogren’s syndrome, uveitis, arthritis and polymyositis are believed to be caused by autoimmune mechanisms.” x4 ‘ Misdirected’ cytolytic activity coupled with the secretion of inflammatory cytokines by infiltrating cells would be sufficient to mediate CNS tissue damage.“’ “‘l However, the nature of such autoreactive T cells, their antigenic specificity and target population has not been defined. Recently, T-cell receptor (TCR) analysis of T cells from a spinal cord lesion has shown limited usage of some VP genes.‘” This is consistent with the observation of oligoclonal and monoclonal expansion of T cells detected in a subgroup of HAM/TSP patients,““.” although the reason for selective VP use has not been defined. Finally, it is possible that both autoimmune and cytotoxic mechanisms contribute to the pathogenesis of HAM/T% Specific patterns of cell migration may be directed by adhesion molecules aberrantly expressed on activated HTLV-I-infected T cells, interacting with specific receptors on vascular endothelial cells.“” However, both the cytotoxic and autoimmune models fail to explain why the thoracic spinal cord is a preferential target site for tissue infiltration and inflammation, or the characteristic spastic paresis seen with this disorder. TREATMENT HTLV-I-associated paraparesis

myelopathyltropical

spastic

Because of the inflammatory nature of the HAM/ TSP, glucocorticoids were among the first drugs used as treatment for this disease. Generally, high doses of glucocorticoids are followed by a transient

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improvement in the spastic gait and sphincter disturbances. Since chronic use of glucocorticoids results in undesirable side-effects, steroids generally have to be tapered after an average period of 6 months.” Most patients experience a recurrence of symptoms in this period.” In the long term, the often favorable initial response to glucocorticoids does not seem to alter the chronic progressive course of the disease.‘” Danazol has been proposed as an alternative to glucocorticoids in the treatment of HAM/T%” Danazol is an attenuated androgen with both hormonal effects and immunomodulatory activity, which has been used in the clinical management of endometriosis, autoimmune hemolytic anemia. idiopathic thrombocytopenic purpura, and hereditary angioedema for about 30 years.” The anabolic effects of danazol are theoretically more favorable for recovery of motor strength. Favorable effects of danazol become apparent after 4-6 weeks of administration of the drug.‘” As is the case for glucocorticoids, improvement of spastic gait and urinary disturbances are the most prominent beneficial effect.“’ Little is presently known about the recurrence rate of these symptoms during long-term treatment. Side effects of danazol include weight gain, lethargy, amenorrhea, mild elevation of transaminases, and hepatic toxicity, which may respond to a decrease in dosage.“’ The mechanism of danazol action is still poorly understood. Better treatment modalities will be required to seriously impact the disease. In addition. as is the case for other demyelinating diseases, early intervention may be more effective at preserving neurological function. Adult T-cell leukemiallymphoma Multiple chemotherapy combinations have been tried for the treatment of the leukemic and lymphomatous form of ATL with disappointing results.‘” The best available results from a prospective clinical trial using a combination of vincristine, adriamycin, cyclophosphamide, prednisolone, etoposide, vindesine, ranimustine, mitoxantrone and GM-CSF as a supporting factor produce complete remission (CR) in only 36% of the patients and a median survival time of 8 months.‘“’ Furthermore, complete remissions are generally not durable, and relapse is the rule. Occasional long survivors (> 2 years) are seen in some patient series in about 10% of patients treated with combination chemotherapy.“: Survival is associated with achieving a complete remission, and in patients with complete remissions, monoclonal integration of provirus is no longer detected in peripheral blood.“’ One reason given for poor response of ATL is expression of the multidrug resistance gene MDR-1, particularly following relapse.“* The utility of high-dose myeloablative chemotherapy

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and autologous or allogeneic bone marrow or stem-cell transplantation remains to be established. Recently, the combination of interferon-a and zidovudine has been used for the treatment of ATL.‘3”.‘40 Complete remission was achieved in 26% of the patients with a median survival time of 5 months.“” It is particularly interesting that interferona and zidovudine combination was effective in some patients who had previously failed to respond to classical combination chemotherapy. Whether zidovudine is acting as an antiviral or through a direct ‘antineoplastic’ mechanism remains to be established. ATL cells constitutively express the IL-2R a-chain that is recognized by the anti-Tat monoclonal antibody.‘4’ As an attempt to provide a rational treatment approach to ATL, this monoclonal antibody coupled with yttriumyO was administered intravenously in a group of patients with ATL.‘“‘,‘“’ Complete remission was achieved in 2 of 16 cases, partial remission in 7 of 16 patients, and was associated with return to normal levels of serum calcium and improvement in liver function.‘42.‘43 Another strategy that is under investigation is the use of interleukin-2 fused to diphtheria toxin (DAB-IL2).‘44 Other approaches have involved the use of interferon a, p, and Y.‘~~~‘~’ Recombinant interferon a, p, and y have all been shown to have inhibitory effects on viral infection of peripheral blood lymphocytes and on growth of HTLV-I transformed T cells in vitro.‘48 These cytokines are reported to produce complete remission in less than 10% of the cases and only occasional long-term response.‘45~‘47 As in other highgrade non-Hodgkin’s lymphomas, newer consolidation strategies for patients who achieve a complete remission will need to be evaluated. The activity of the interferon-alzidovudine combination suggests a potential role for other antiretrovirals in treatment of ATL. Why an antiretroviral should impact ATL, which is not thought to depend upon active viral replication, is unclear.

SUMMARY

The human T-cell leukemia viruses type I and type II have been implicated in pathogenesis of adult T-cell leukemia/lymphoma (ATL), chronic myelopathy (HAM-TSP), and a variety of autoimmune disorders. Similar to HIV-I/II, HTLV-I/II contains a variety of transacting regulatory genes not seen in other retroviruses. The transcriptional regulatory gene tax may play a role in pathogenesis through effects on select cellular promoters, leading to T-cell proliferation. In HAM-TSP, an autoimmune or cytotoxic mechanism may lead to neurodegenerative disease. Treatment for

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