[Frontiers in Bioscience 14, 3935-3941, January 1, 2009]
Linda Zane1, David Sibon1, Franck Mortreux1, Eric Wattel1, 2
1
TABLE OF CONTENTS
1. ABSTRACT
As other deltaretroviruses HTLV-1 replication in vivo includes a first short step of reverse transcription that is followed by the persistent clonal expansion of infected cells. In vivo these cells include the CD4+ and CD8+ lymphocytes yet the virus induces adult T cell leukemia/lymphoma (ATLL) that is regularly of the CD4+ phenotype. Cloned infected cells from individuals without malignancy possess a dramatic increase in spontaneous proliferation, which predominated with CD8+ lymphocytes and depends on the amount of tax mRNA. In fact, the clonal expansion of HTLV-1 positive CD8+ and CD4+ lymphocytes relies on two distinct mechanisms: infection prevented cell death in the former whereas recruiting the latter into the cell cycle. Furthermore infected tax-expressing CD4+ lymphocytes cumulate cellular defects characteristic of genetic instability. Therefore, HTLV-1 infection establishes a preleukemic phenotype that is restricted to CD4+ infected clones. Investigating the mechanisms underlying apoptosis, cell cycling and DNA repair in cloned cells from naturally infected individuals will permit to deciphering the molecular pathogenesis of HTLV-1 infection.
2. INTRODUCTION
Retroviruses are unique as they exist as DNA and/or RNA species. Their polymerases are reverse transcriptases devoided of 3' exonucleolytic activity and genetic variability is thereby a part of their way of life (1, 2). Among retroviruses, deltaretroviruses possess an additional mechanism of replication that accompanies an original way of genetic variability. In addition to reverse transcriptase that generates an error rate in the same range as those of other retroviruses, these lymphotropic viruses encode regulatory proteins that interfere with many host cell pathways including cell cycle, apoptosis and DNA repair (3). This results in the persistent clonal expansion of infected cells and generates a significant level of genetic variability resulting from somatic mutations of the proviral sequence (4-6).
Deltaretroviruses include human T-cell leukemia viruses type -1 (7) and -2 (HTLV-1 and 2) (8), the recently discovered HTLV-3 (9) and -4 (10), simian T-cell leukemia viruses (STLV) (11), and the bovine leukemia virus (BLV) (12). They infect vertebrates and cause leukemia and lymphoma. Two steps characterize the course of deltaretroviruses infection in vivo, including a brief period of primary infection that is followed by the chronic and persistent infection (5, 6, 13, 14). After experimental infection, primary infection starts with viral contamination and, at least for HTLV-1 in squirrel monkey (Saimiri sciureus) and BLV in sheep, finishes 1-6 months later, as soon as both humoral and cellular antiviral host immune responses have been mounted (14, 15). The second phase of the infection encompasses the remaining lifespan of infected organisms. It could be clinically latent or associated with the development of inflammatory or malignant diseases. HTLV-1 infects CD4+ and CD8+ lymphocytes in vivo. In a recent work, we found that the cell-associated dissemination of the virus in vivo pertains for both lymphocytes subtypes but relies on specific mechanisms with respect to the cellular phenotype. Clonal expansion of HTLV-1 infected cells was found to result from the accumulation of CD8+ lymphocytes or from the proliferation of CD4+ cells. Here we review the main virological and pathogenic consequences of these findings.
3. CD4+ AND CD8+ T LYMPHOCYTES ARE THE MAJOR HTLV-1 RESERVOIR
In vitro, HTLV-1 infects a wide range of cells (16) including several non lymphoid tumor cell lines such as human osteogenic sarcoma cells (17), lung cells, cervical carcinoma cells (HeLa) (18), human gastric HGC-27 cells (19), human promyelocytic leukaemia HL60 cells (20) as well as primary endothelial cells (21), monocyte, microglial cells (22), and mammary epithelial cells (23). In vivo, HTLV-1 intercellular passage, i.e. horizontal, reverse-transcription-based replication, requires a close cell-to-cell contact via the formation of the recently described "virological synapse" between the infected and target cells (24). In addition in vivo, HTLV-1 is found primarily in CD4+ and CD8+ (25) T lymphocytes and less frequently in other cell types such as monocytes, endothelial cells and dendritic cells (26, 27).
Recently the glucose transporter GLUT1 was found as a receptor for HTLV-1 (16), mediating viral binding and entry. In vitro, GLUT-1 is found on all mammalian cell lines (28) whereas in vivo, its expression characterizes a restricted number of cell types including activated T cells (29). This contributes to explain the HTLV-1 tropism in vivo. In addition to a cell-specific expression of its receptor, the HTLV-1 tropism might depend on post-entry events. After cell entry, retrovirus envelope interacts with its specific receptor and thereby blocks further superinfection. This could also alter the function of the receptor. Indeed, the interaction between the HTLV-1 encoded GP46 with GLUT-1 negatively interferes with glucose entry and therefore could compromise cell viability, especially in cells having a high metabolic rate. Accordingly it is possible that in vivo, HTLV can initially spread with a large tropism but with the subsequent elimination of cells having a high metabolic rate (16). Conversely, after proviral integration, a reduced level of envelope expression might subsequently permit glucose intake and thereby help cell viability and persistent infection.
Neuropilin 1 (NRP-1) is also involved in HTLV-1 entry and may be an additional cell receptor for the virus (30). NRP1 is expressed on a broad range of cell lines from various origins in vitro and over-expressed upon T-cell activation (30). In contrast with GLUT1, NRP1 specifically concentrates in "virological synapses" but currently, the respective contributions of GLUT1 and NRP1 to the binding and fusion steps of the HTLV-1 entry process remain unknown. Other molecules on the cell surface may be critical for HTLV-1 env-mediated binding and/or fusion such as heparan sulfate proteoglycans and certain integrins, including ICAM-1, ICAM-3 and V-CAM (31, 32). These latter may act as cofactors for HTLV-1 induced cell fusion whereas HSPGs have been reported to play a role in the binding of HTLV-1 to target cells and to contribute to HTLV-1 infection of primary CD4+ T cells (33, 34).
4. CLONAL EXPANSION OF HTLV-1 INFECTED T CELLS
Originally it was thought that HTLV-1 integration was polyclonal in HTLV-1 associated myelopathy (HAM-TSP) (35). Thereafter, it was shown also by Southern Blotting that TSP/HAM was accompanied by occasional oligoclonal expansion of infected cells (36). Another team examined variations in the T cell receptor (TCR) Vα and Vβ chains in peripheral blood mononuclear cells (PBMC) derived from patients with HAM/TSP and evidenced the proliferation of anti-HTLV-1 specific CD8+ T lymphocytes without distinguishing infected from uninfected cells (37). Finally, by using sensitive PCR-derived techniques such as linker mediated PCR or inverse PCR (38-40), it was possible to provide evidence of clonal expansion of HTLV-1 bearing T cells in all infected individuals. This route of replication was found to pertain at all stages of the infection and to characterize both CD4+ and CD8+ infected T lymphocytes (41, 42). As 2n proviral copies are generated for a given clone after n cell divisions, few cell-associated replication cycles are sufficient to mount elevated proviral loads. This contributes to explain the combination of high proviral loads observed in infected individuals with the very low cell-to-cell transmission rate and the apparent low genetic drift of the virus (40, 43).
5. PROVIRAL GENETIC VARIABILITY PARALLELS CLONAL EXPANSION
HTLV-1 genetic variation results mainly from post-integration events that consist in somatic mutations of the proviral sequence occurring during clonal expansion (4). Surprisingly, the frequency of somatic mutations was much higher than that expected as the 3'RU5 mutation frequency was found to be 600 times higher than that for the HTLV-1 reverse transcription (4). At steady state, 60% of HTLV-1 positive clones include 8% to 80% of infected cells harboring a mutated HTLV-1 provirus, without evidence for reverse transcription-associated mutations. Interestingly both the provirus and the cellular genome display the same process of somatic mutations (4). The experimental infection of squirrel monkeys (Saimiri sciureus) and sheep with HTLV-1 and BLV, respectively, evidenced that deltaretrovirus infection is a two-step process that includes an early and transient phase of reverse transcription followed by the persistent multiplication of infected cells by clonal expansion (6, 14). For the first time, RT-dependent substitutions could be evidenced for a deltaretrovirus by analyzing BLV replication during the first weeks following experimental sheep infection (6). The two main diseases related to HTLV-1 are TSP/HAM and ATLL. ATLL is malignant CD4+ monoclonal lymphoproliferative disease (44) while TSP/HAM is a neurological disorder characterized by the infiltration of CD4+ and CD8+ T cells in the thoracic spinal cord (45). Both clonal expansion and somatic mutations have been found to participate to the pathogenesis of these conditions.
6. PATHOGENICAL AND CLINICAL IMPLICATIONS IN ATLL
ATLL occurs after a prolonged period of clinical latency lasting, on average, greater than 30 years (46). As in other lymphoid malignancies, malignant ATLL cells frequently infiltrate skin, bone, bone marrow, and other organs in vivo (44). This results from the cellular transport of the integrated provirus to the corresponding sites, as confirmed by molecular studies (41). The tumor clone is usually monoclonal for HTLV-1 integration (47) and is accompanied by a background of polyclonally expanded and untransformed cells (41). During the period of clinical latency preceding tumor onset, infected cells express the HTLV-1-encoded Tax oncoprotein (48, 49), which is known for possessing a pleiotropic effect on cellular metabolism, particularly on cell cycle, DNA repair and apoptosis (49). We recently investigated this preleukemic period of the infection in an animal model, the sheep model of BLV infection, which permits to reconstitute the clonal history of preleukemic cells, from the experimental infection to the tumor stage. Premalignant clones, identified by the integration site of the provirus, are early and clearly distinguished from other virus-exposed cells on the basis of their degree of clonal expansion and genetic instability (5). Detectable as early as 15 days after the beginning of virus exposure, premalignant cells display a two-step pattern of extensive clonal expansion together with a mutation load strongly higher than that of other virus-exposed cells that remain untransformed during the lifespan of animals. There is no fixation of somatic mutations over time, suggesting that they regularly lead to cellular death, partly contributing to maintain a normal lymphocyte count during the prolonged premalignant stage. This equilibrium is regularly broken after a period of 18.5 to 60 months of clinical latency, when a dramatic decrease in the genetic instability of premalignant cells coincides with a rapid increase in lymphocyte count and lymphoma onset.
7. PATHOGENICAL AND CLINICAL IMPLICATIONS IN TSP/HAM
HAM/TSP is a chronic debilitating inflammatory disease of the central nervous system, characterized by axonal damage and demyelination, most pronounced in the midthoracic spinal cord. HAM/TSP is characterized by high proviral loads that result from the extensive proliferation of a restricted number of infected clones (50). One of the main pathological features of the disease is a chronic inflammatory process that predominates in the lateral and posterior columns of the spinal cord in the thoracic region. Lesions include CD4+ and CD8+ cellular infiltrates that correspond to infected and uninfected cells. As infected lymphocytes sharing the same flanking sequences are regularly detected in both the cerebrospinal fluid and the peripheral blood of patients with HAM/TSP, it was concluded that HTLV-1 crosses the blood-brain barrier by way of the migration of HTLV-1 infected lymphocytes (51). Similarly, HTLV-1 infected T cells infiltrate the aqueous humor, the synovial fluid, and the alveolar liquid of patients with uveitis, arthropathy, and alveolitis, respectively, with the evidence of a cell associated transport of the virus in each of these situations (Wattel E, unpublished works). Similar results have been obtained with various organs in the Squirrel Monkey experimentally infected with HTLV-1 positive cells (14). Together these data indicate that the clonal expansion of infected cells helps these cells to migrate in body compartment where they contribute to trigger inflammatory damage.
8. WHICH MECHANISMS UNDERLIE CLONAL EXPANSION?
From the studies detailed above, it appears that high provirus loads resulting from clonal expansion of HTLV-1 bearing T cells are associated with viral dissemination, inflammatory diseases and preleukemic states. As a corollary, the somatic mutation rate parallels the level of clonal expansion and culminates at the symptomatic stages of the infection (5, 6). Therefore, clonal expansion and somatic substitutions play a critical role in the pathogenesis of HTLV-1 associated diseases. Knowing the mechanisms that underlie these two processes will help to understand and target HTLV-1 diseases.
Schematically, the 2 main mechanisms contributing to clonal expansion are cell accumulation and cell proliferation. The former relies on the regulation of the cell cycle and the latter on the regulation of apoptosis. We recently investigated these two cell processes in CD4+ and CD8+ cells (52). This was done by developing a cellular model of HTLV-1 replication through clonal expansion, by T-cell limiting dilution cloning of cells derived from HLTV-1 infected patients without malignancy (52). Cloning uninfected and naturally infected CD4+ and CD8+ T cells deriving from the same infected individuals permitted to clearly compare the effects of the infection on CD4+ and CD8+ cells. Results indicated that the clonal expansion of HTLV-1 positive cells relies on 2 clearly distinct mechanisms for CD4+ and CD8+ lymphocytes. Indeed HTLV-1 infection propels CD4+ infected T cells into the cell cycle while preventing cell death in CD8+ infected cells. In addition, infected tax-expressing CD4+ lymphocytes cumulate cellular defects characteristic of genetic instability.
In vivo, HTLV-1 infected CD4+ and CD8+ lymphocytes display the same pattern of clonal expansion (52). The higher degree of in vivo clonal expansion in infected CD4+ lymphocytes might well contribute to selecting malignant events, as a high level of clonal expansion of deltaretrovirus-infected cells is the signature of premalignant clones in vivo (5, 6, 14). Furthermore, ex vivo, cloned CD4+ HTLV-1+ lymphocytes accumulate numerous cellular defects, including multinuclearity, chromatin bridges and nuclear abnormalities that characterize genetic instability (53-59). One can propose that, together with these cellular abnormalities and the extensive oligo/polyclonal expansion observed in vivo, cell cycling, which is restricted to HTLV-1+-CD4+ untransformed clones in a tax-dependent manner, is implicated in promoting HTLV-1 associated lymphoid malignancies and establishes a preleukemic phenotype that is restricted to CD4+ infected cells. By contrast, the CD8+-restricted inhibition of apoptosis, which is independent of tax expression, might favor CD8+-dependent control of the infection (60) and inflammatory processes involved in the pathogenesis of TSP/HAM, uveitis or infective dermatitis. The figure 1 summarizes the behaviors of CD4+ versus CD8+ cells upon HTLV-1 infection. As upon infection CD4+ cells proliferate while CD8+ cells accumulate, the number of cell divisions necessary for obtaining the same number of cells appears significantly higher for generating and maintaining a CD4+ clone when compared to a CD8+ clone having the same cell count. As these infected CD4+ cells seem impaired for the reparation of DNA damages (61), this excess of mitosis might expose the clone for malignant transformation.
9. MOLECULAR CAUSES UNDERLYING CLONAL EXPANSION IN VIVO
Numerous studies have investigated the interplay between HTLV-1, cell cycling, apoptosis, and genetic instability. Although some conflicting data have been published, it appears that this virus is antiapoptotic, promoting cell cycling and impairing DNA repair (61). However these effects have been evidenced in cell lines or in cells expressing virus-encoded proteins. Having observed that the effect of the infection on apoptosis, cell cycling and genetic instability depends on the lymphocyte phenotype, we now investigate the molecular mechanisms underlying these three precancerous processes in CD4+ versus CD8+ cells deriving from naturally infected individuals. We hypothesize that by taking into account these phenotype-dependent effects of the infection on cell behavior in vivo, the proposed experimental strategy will permit to gather pertinent data for better understanding HTLV-1 pathogenesis and for targeting pertinent defects.
10. REFERENCES
1. Drake, J. W.: Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci U S A, 90, 4171-5(1993) doi:10.1073/pnas.90.9.4171
doi:10.1073/pnas.90.9.4171
2. Drake, J. W. & J. J. Holland: Mutation rates among RNA viruses. Proc Natl Acad Sci U S A, 96, 13910-13913(1999) doi:10.1073/pnas.96.24.13910
doi:10.1073/pnas.96.24.13910
3. Philpott, S. M. & G. C. Buehring: Defective DNA repair in cells with human T-cell leukemia/bovine leukemia viruses: role of tax gene. J Natl Cancer Inst, 91, 933-42(1999) doi:10.1093/jnci/91.11.933
doi:10.1093/jnci/91.11.933
PMid:10359545
4. Mortreux, F., I. Leclercq, A. Gabet, A. Leroy, E. Westhof, A. Gessain, S. Wain-Hobson & E. Wattel: Somatic Mutation in Human T-Cell Leukemia Virus Type 1 Provirus and Flanking Cellular Sequences During Clonal Expansion In Vivo. J Natl Cancer Inst, 93, 367-377(2001) doi:10.1093/jnci/93.5.367
doi:10.1093/jnci/93.5.367
PMid:11238698
5. Moules, V., C. Pomier, D. Sibon, A. S. Gabet, M. Reichert, P. Kerkhofs, L. Willems, F. Mortreux & E. Wattel: Fate of premalignant clones during the asymptomatic phase preceding lymphoid malignancy. Cancer Res, 65, 1234-43(2005) doi:10.1158/0008-5472.CAN-04-1834
doi:10.1158/0008-5472.CAN-04-1834
PMid:15735007
6. Pomier, C., M. T. Sanchez Alcaraz, C. Debacq, A. Lancon, P. Kerkhofs, L. Willems, E. Wattel & F. Mortreux: Early and transient reverse transcription during primary deltaretroviral infection of sheep. Retrovirology, 5, 16(2008) doi:10.1186/1742-4690-5-16
doi:10.1186/1742-4690-5-16
PMid:18241341 PMCid:2270868
7. Poiesz, B. J., F. W. Ruscetti, A. F. Gazdar, P. A. Bunn, J. D. Minna & R. C. Gallo: Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A, 77, 7415-7421(1980) doi:10.1073/pnas.77.12.7415
doi:10.1073/pnas.77.12.7415
8. Kalyanaraman, V. S., M. G. Sarngadharan, M. Robert-Guroff, I. Miyoshi, D. Golde & R. C. Gallo: A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science, 218, 571-3.(1982) doi:10.1126/science.6981847
doi:10.1126/science.6981847
PMid:6981847
9. Calattini, S., S. A. Chevalier, R. Duprez, S. Bassot, A. Froment, R. Mahieux & A. Gessain: Discovery of a new human T-cell lymphotropic virus (HTLV-3) in Central Africa. Retrovirology, 2, 30(2005) doi:10.1186/1742-4690-2-30
doi:10.1186/1742-4690-2-30
PMid:15882466 PMCid:1142341
10. Wolfe, N. D., W. Heneine, J. K. Carr, A. D. Garcia, V. Shanmugam, U. Tamoufe, J. N. Torimiro, A. T. Prosser, M. Lebreton, E. Mpoudi-Ngole, F. E. McCutchan, D. L. Birx, T. M. Folks, D. S. Burke & W. M. Switzer: Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters. Proc Natl Acad Sci U S A, 102, 7994-9(2005) doi:10.1073/pnas.0501734102
doi:10.1073/pnas.0501734102
11. Meertens, L., R. Mahieux, P. Mauclere, J. Lewis & A. Gessain: Complete sequence of a novel highly divergent simian T-cell lymphotropic virus from wild-caught red-capped mangabeys (Cercocebus torquatus) from Cameroon: a new primate T-lymphotropic virus type 3 subtype. J Virol, 76, 259-68.(2002) doi:10.1128/JVI.76.1.259-268.2002
doi:10.1128/JVI.76.1.259-268.2002
PMid:11739691 PMCid:135714
12. Ferrer, J. F., D. A. Abt, D. M. Bhatt & R. R. Marshak: Studies on the relationship between infection with bovine C-type virus, leukemia, and persistent lymphocytosis in cattle. Cancer Res, 34, 893-900.(1974)
13. Kazanji, M., A. Ureta-Vidal, S. Ozden, F. Tangy, B. de Thoisy, L. Fiette, A. Talarmin, A. Gessain & G. de The: Lymphoid organs as a major reservoir for human T-cell leukemia virus type 1 in experimentally infected squirrel monkeys (Saimiri sciureus): provirus expression, persistence, and humoral and cellular immune responses (In Process Citation). J Virol, 74, 4860-7(2000) doi:10.1128/JVI.74.10.4860-4867.2000
doi:10.1128/JVI.74.10.4860-4867.2000
PMid:10775625 PMCid:112009
14. Mortreux, F., M. Kazanji, A. S. Gabet, B. de Thoisy & E. Wattel: Two-step nature of human T-cell leukemia virus type 1 replication in experimentally infected squirrel monkeys (Saimiri sciureus) (In Process Citation). J Virol, 75, 1083-9(2001) doi:10.1128/JVI.75.2.1083-1089.2001
doi:10.1128/JVI.75.2.1083-1089.2001
PMid:11134325 PMCid:114008
15. Ward, W. H., C. K. Dimmock & F. W. Eaves: T lymphocyte responses of sheep to bovine leukaemia virus infection. Immunol Cell Biol, 70 (Pt 5), 329-36(1992) doi:10.1038/icb.1992.42
doi:10.1038/icb.1992.42
PMid:1335963
16. Manel, N., F. J. Kim, S. Kinet, N. Taylor, M. Sitbon & J. L. Battini: The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell, 115, 449-59(2003) doi:10.1016/S0092-8674(03)00881-X
doi:10.1016/S0092-8674(03)00881-X
PMid:14622599
17. Clapham, P., K. Nagy, R. Cheingsong-Popov, M. Exley & R. A. Weiss: Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line. Science, 222, 1125-7(1983) doi:10.1126/science.6316502
doi:10.1126/science.6316502
PMid:6316502
18. Hayami, M., H. Tsujimoto, A. Komuro, Y. Hinuma & K. Fujiwara: Transmission of adult T-cell leukemia virus from lymphoid cells to non-lymphoid cells associated with cell membrane fusion. Gann, 75, 99-102(1984)
19. Akagi, T., T. Yoshino, M. Motoi, H. Takata, S. Yano, I. Miyoshi, T. Oka & Y. Ohtsuki: Isolation of virus-producing transformants from human gastric cancer cell line, HGC-27, infected with human T-cell leukemia virus type I. Jpn J Cancer Res, 79, 836-42(1988)
20. Hiramatsu, K., M. Masuda & H. Yoshikura: Mode of transmission of human T-cell leukemia virus type I (HTLV I) in a human promyelocytic leukemia HL60 cell. Int J Cancer, 37, 601-6(1986) doi:10.1002/ijc.2910370420
doi:10.1002/ijc.2910370420
21. Ho, D. D., T. R. Rota & M. S. Hirsch: Infection of human endothelial cells by human T-lymphotropic virus type I. Proc Natl Acad Sci U S A, 81, 7588-90(1984) doi:10.1073/pnas.81.23.7588
doi:10.1073/pnas.81.23.7588
22. Hoffman, P. M., S. Dhib-Jalbut, J. A. Mikovits, D. S. Robbins, A. L. Wolf, G. K. Bergey, N. C. Lohrey, O. S. Weislow & F. W. Ruscetti: Human T-cell leukemia virus type I infection of monocytes and microglial cells in primary human cultures. Proc Natl Acad Sci U S A, 89, 11784-8(1992) doi:10.1073/pnas.89.24.11784
doi:10.1073/pnas.89.24.11784
23. LeVasseur, R. J., S. O. Southern & P. J. Southern: Mammary epithelial cells support and transfer productive human T-cell lymphotropic virus infections. J Hum Virol, 1, 214-23(1998)
24. Igakura, T., J. C. Stinchcombe, P. K. Goon, G. P. Taylor, J. N. Weber, G. M. Griffiths, Y. Tanaka, M. Osame & C. R. Bangham: Spread of HTLV-I Between Lymphocytes by Virus-Induced Polarization of the Cytoskeleton. Science, 299, 1713-6(2003) doi:10.1126/science.1080115
doi:10.1126/science.1080115
PMid:12589003
25. Nagai, M., M. B. Brennan, J. A. Sakai, C. A. Mora & S. Jacobson: CD8(+) T cells are an in vivo reservoir for human T-cell lymphotropic virus type I. Blood, 98, 1858-61.(2001) doi:10.1182/blood.V98.6.1858
doi:10.1182/blood.V98.6.1858
PMid:11535522
26. Koyanagi, Y., Y. Itoyama, N. Nakamura, K. Takamatsu, J. Kira, T. Iwamasa, I. Goto & N. Yamamoto: In vivo infection of human T-cell leukemia virus type I in non-T cells. Virology, 196, 25-33(1993) doi:10.1006/viro.1993.1451
doi:10.1006/viro.1993.1451
PMid:8356797
27. Macatonia, S. E., J. K. Cruickshank, P. Rudge & S. C. Knight: Dendritic cells from patients with tropical spastic paraparesis are infected with HTLV-1 and stimulate autologous lymphocyte proliferation. AIDS Res Hum Retroviruses, 8, 1699-706(1992)
28. Jones, K. S., C. Petrow-Sadowski, D. C. Bertolette, Y. Huang & F. W. Ruscetti: Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells. J Virol, 79, 12692-702(2005) doi:10.1128/JVI.79.20.12692-12702.2005
doi:10.1128/JVI.79.20.12692-12702.2005
PMid:16188972 PMCid:1235841
29. Manel, N., S. Kinet, J. L. Battini, F. J. Kim, N. Taylor & M. Sitbon: The HTLV receptor is an early T cell activation marker whose expression requires de novo protein synthesis. Blood(2002)
30. Ghez, D., Y. Lepelletier, S. Lambert, J. M. Fourneau, V. Blot, S. Janvier, B. Arnulf, P. M. van Endert, N. Heveker, C. Pique & O. Hermine: Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J Virol, 80, 6844-54(2006) doi:10.1128/JVI.02719-05
doi:10.1128/JVI.02719-05
PMid:16809290 PMCid:1489069
31. Daenke, S., S. A. McCracken & S. Booth: Human T-cell leukaemia/lymphoma virus type 1 syncytium formation is regulated in a cell-specific manner by ICAM-1, ICAM-3 and VCAM-1 and can be inhibited by antibodies to integrin beta2 or beta7. J Gen Virol, 80 (Pt 6), 1429-36(1999)
32. Hildreth, J. E., A. Subramanium & R. A. Hampton: Human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation mediated by vascular cell adhesion molecule-1: evidence for involvement of cell adhesion molecules in HTLV-1 biology. J Virol, 71, 1173-80(1997)
33. Jones, K. S., S. Akel, C. Petrow-Sadowski, Y. Huang, D. C. Bertolette & F. W. Ruscetti: Induction of human T cell leukemia virus type I receptors on quiescent naive T lymphocytes by TGF-beta. J Immunol, 174, 4262-70(2005)
34. Pinon, J. D., P. J. Klasse, S. R. Jassal, S. Welson, J. Weber, D. W. Brighty & Q. J. Sattentau: Human T-cell leukemia virus type 1 envelope glycoprotein gp46 interacts with cell surface heparan sulfate proteoglycans. J Virol, 77, 9922-30(2003) doi:10.1128/JVI.77.18.9922-9930.2003
doi:10.1128/JVI.77.18.9922-9930.2003
PMid:12941902 PMCid:224595
35. Gessain, A., F. Saal, O. Gout, M. T. Daniel, G. Flandrin, G. de The, J. Peries & F. Sigaux: High human T-cell lymphotropic virus type I proviral DNA load with polyclonal integration in peripheral blood mononuclear cells of French West Indian, Guianese, and African patients with tropical spastic paraparesis. Blood, 75, 428-33(1990)
36. Furukawa, Y., J. Fujisawa, M. Osame, M. Toita, S. Sonoda, R. Kubota, S. Ijichi & M. Yoshida: Frequent clonal proliferation of human T-cell leukemia virus type 1 (HTLV-1)-infected T cells in HTLV-1-associated myelopathy (HAM-TSP). Blood, 80, 1012-1016(1992)
37. Furukawa, K., M. Mori, N. Ohta, H. Ikeda, H. Shida, K. Furukawa & H. Shiku: Clonal expansion of CD8+ cytotoxic T lymphocytes against human T cell lymphotropic virus type I (HTLV-I) genome products in HTLV-I-associated myelopathy/tropical spastic paraparesis patients. J Clin Invest, 94, 1830-9(1994) doi:10.1172/JCI117532
doi:10.1172/JCI117532
PMid:7962528 PMCid:294583
38. Cavrois, M., A. Gessain, S. Wain-Hobson & E. Wattel: Proliferation of HTLV-1 infected circulating cells in vivo in all asymptomatic carriers and patients with TSP/HAM. Oncogene, 12, 2419-2423(1996)
39. Takemoto, S., M. Matsuoka, K. Yamaguchi & K. Takatsuki: A novel diagnostic method of adult T-cell leukemia: monoclonal integration of human T-cell lymphotropic virus type I provirus DNA detected by inverse polymerase chain reaction. Blood, 84, 3080-3085(1994)
40. Wattel, E., J. P. Vartanian, C. Pannetier & S. Wain-Hobson: Clonal expansion of human T-cell leukemia virus type I-infected cells in asymptomatic and symptomatic carriers without malignancy. J Virol, 69, 2863-2668(1995)
41. Cavrois, M., S. Wain-Hobson, A. Gessain, Y. Plumelle & E. Wattel: Adult T-cell leukemia/lymphoma on a background of clonally expanding human T-cell leukemia virus type-1-positive cells. Blood, 88, 4646-4650(1996)
42. Wattel, E., M. Cavrois, A. Gessain & S. Wain-Hobson: Clonal expansion of infected cells - a way of life for HTLV-1. J Acquir Immune Defic Syndr Hum Retrovirol, 13 (SUPPL 1), 92-99(1996) doi:10.1097/00042560-199600001-00016
doi:10.1097/00042560-199600001-00016
PMid:8797710
43. Wattel, E., M. Mariotti, F. Agis, E. Gordien, F. F. Le Coeur, L. Prin, P. Rouger, I. S. Chen, S. Wain-Hobson & J. J. Lefrere: Quantification of HTLV-1 proviral copy number in peripheral blood of symptomless carriers from the French West Indies. J Acquir Immune Defic Syndr, 5, 943-946(1992)
44. Takatsuki, K., K. Yamaguchi, F. Kawano, T. Hattori, H. Nishimura, H. Tsuda, I. Sanada, K. Nakada & Y. Itai: Clinical diversity in adult T-cell leukemia-lymphoma. Cancer Res, 45, 4644s-4645s.(1985)
45. Orland, J. R., J. Engstrom, J. Fridey, R. A. Sacher, J. W. Smith, C. Nass, G. Garratty, B. Newman, D. Smith, B. Wang, K. Loughlin & E. L. Murphy: Prevalence and clinical features of HTLV neurologic disease in the HTLV Outcomes Study. Neurology, 61, 1588-94(2003)
46. Blattner, W. A.: Human T-lymphotrophic viruses and diseases of long latency. Ann Intern Med, 111, 4-6(1989)
47. Yoshida, M., M. Seiki, K. Yamaguchi & K. Takatsuki: Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci U S A, 81, 2534-2537(1984) doi:10.1073/pnas.81.8.2534
doi:10.1073/pnas.81.8.2534
48. Furukawa, Y., M. Osame, R. Kubota, M. Tara & M. Yoshida: Human T-cell leukemia virus type-1 (HTLV-1) Tax is expressed at the same level in infected cells of HTLV-1-associated myelopathy or tropical spastic paraparesis patients as in asymptomatic carriers but at a lower level in adult T-cell leukemia cells. Blood, 85, 1865-70(1995)
49. Yoshida, M.: Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol, 19, 475-96(2001) doi:10.1146/annurev.immunol.19.1.475
doi:10.1146/annurev.immunol.19.1.475
PMid:11244044
50. Leclercq, I., F. Mortreux, M. Cavrois, A. Leroy, A. Gessain, S. Wain-Hobson & E. Wattel: Host sequences flanking the human T-cell leukemia virus type 1 provirus In vivo. J Virol, 74, 2305-2312(2000) doi:10.1128/JVI.74.5.2305-2312.2000
doi:10.1128/JVI.74.5.2305-2312.2000
PMid:10666261 PMCid:111712
51. Cavrois, M., A. Gessain, O. Gout, S. Wain-Hobson & E. Wattel: Common Human T Cell Leukemia Virus Type 1 (HTLV-1) Integration Sites in Cerebrospinal Fluid and Blood Lymphocytes of Patients with HTLV-1- Associated Myelopathy/Tropical Spastic Paraparesis Indicate that HTLV-1 Crosses the Blood-Brain Barrier via Clonal HTLV-1-Infected Cells. J Infect Dis, 182, 1044-1050(2000) doi:10.1086/315844
doi:10.1086/315844
PMid:10979898
52. Sibon, D., A. S. Gabet, M. Zandecki, C. Pinatel, J. Thete, M. H. Delfau-Larue, S. Rabaaoui, A. Gessain, O. Gout, S. Jacobson, F. Mortreux & E. Wattel: HTLV-1 propels untransformed CD4 lymphocytes into the cell cycle while protecting CD8 cells from death. J Clin Invest, 116, 974-83(2006) doi:10.1172/JCI27198
doi:10.1172/JCI27198
PMid:16585963 PMCid:1421359
53. Gisselsson, D., J. Bjork, M. Hoglund, F. Mertens, P. Dal Cin, M. Akerman & N. Mandahl: Abnormal nuclear shape in solid tumors reflects mitotic instability. Am J Pathol, 158, 199-206(2001)
54. Gisselsson, D. & M. Hoglund: Connecting mitotic instability and chromosome aberrations in cancer--can telomeres bridge the gap? Semin Cancer Biol, 15, 13-23(2005) doi:10.1016/j.semcancer.2004.09.002
doi:10.1016/j.semcancer.2004.09.002
PMid:15613284
55. Gisselsson, D., T. Jonson, A. Petersen, B. Strombeck, P. Dal Cin, M. Hoglund, F. Mitelman, F. Mertens & N. Mandahl: Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci U S A, 98, 12683-8(2001) doi:10.1073/pnas.211357798
doi:10.1073/pnas.211357798
56. Gisselsson, D., T. Jonson, C. Yu, C. Martins, N. Mandahl, J. Wiegant, Y. Jin, F. Mertens & C. Jin: Centrosomal abnormalities, multipolar mitoses, and chromosomal instability in head and neck tumours with dysfunctional telomeres. Br J Cancer, 87, 202-7(2002) doi:10.1038/sj.bjc.6600438
doi:10.1038/sj.bjc.6600438
57. Gisselsson, D., L. Pettersson, M. Hoglund, M. Heidenblad, L. Gorunova, J. Wiegant, F. Mertens, P. Dal Cin, F. Mitelman & N. Mandahl: Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci U S A, 97, 5357-62(2000) doi:10.1073/pnas.090013497
doi:10.1073/pnas.090013497
58. O'Sullivan, J. N., M. P. Bronner, T. A. Brentnall, J. C. Finley, W. T. Shen, S. Emerson, M. J. Emond, K. A. Gollahon, A. H. Moskovitz, D. A. Crispin, J. D. Potter & P. S. Rabinovitch: Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet, 32, 280-4(2002) doi:10.1038/ng989
doi:10.1038/ng989
PMid:12355086
59. Pennarun, G., C. Granotier, L. R. Gauthier, D. Gomez, F. Hoffschir, E. Mandine, J. F. Riou, J. L. Mergny, P. Mailliet & F. D. Boussin: Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands. Oncogene, 24, 2917-28(2005) doi:10.1038/sj.onc.1208468
doi:10.1038/sj.onc.1208468
PMid:15735722
60. Hanon, E., J. C. Stinchcombe, M. Saito, B. E. Asquith, G. P. Taylor, Y. Tanaka, J. N. Weber, G. M. Griffiths & C. R. Bangham: Fratricide among CD8(+) T lymphocytes naturally infected with human T cell lymphotropic virus type I. Immunity, 13, 657-64.(2000) doi:10.1016/S1074-7613(00)00065-0
doi:10.1016/S1074-7613(00)00065-0
PMid:11114378
61. Marriott, S. J. & O. J. Semmes: Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response. Oncogene, 24, 5986-95(2005) doi:10.1038/sj.onc.1208976
doi:10.1038/sj.onc.1208976
PMid:16155605
Key Words: HTLV-1, HTLV-2, STLV, BLV, Deltaretroviruses, Leukemia, Lymphoma, Replication, Apoptosis, Cell cycle, Review
Send correspondence to: Eric Wattel, Oncovirologie et Biotherapies, FRE3011-CNRS-Universite Claude Bernard, Centre Leon Berard, 28, rue Laennec 69373 Lyon cedex 08 France, Tel: 33478782669, Fax: 33478782717, E-mail: wattel@lyon.fnclcc.fr