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REVIEW Molecular and Cellular Aspects of HTLV-1 Associated Leukemia (2003) 17, 26–38 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu REVIEW Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo F Mortreux1,3, A-S Gabet1 and E Wattel1,2 1Unite´ d’Oncogene`se Virale, UMR5537 CNRS-Universite´ Claude Bernard, Centre Le´ ´on Be´rard, Lyon, France; and 2Service d’He´matologie, Pavillon E, Hoˆpital Edouard Herriot, Lyon, France Most cancers and leukemias are preceded by a prolonged per- leukemia/lymphoma (ATLL).2,3 Furthermore, this virus has iod of clinical latency during which cellular, chromosomal and been associated with the development of a chronic progress- molecular aberrations help move normal cell towards the malig- ive neuromyelopathy (tropical spastic paraparesis (TSP)/HTLV- nant phenotype. The problem is that premalignant cells are 4 usually indistinguishable from their normal counterparts, ther- 1-associated myelopathy (HAM)), and, to a lesser extent, to eby ruling out the possibility to investigate the events that a variety of inflammatory diseases.5–9 govern early leukemogenesis in vivo. Adult T cell Among the 15–25 million individuals infected worldwide, leukemia/lymphoma (ATLL) is a T cell malignancy that occurs approximately 3% to 5% will develop ATLL, depending on as after a 40–60-year period of clinical latency in about 3–5% of yet unknown cofactors. ATLL harbors different clinical fea- HTLV-1-infected individuals. ATLL cells are monoclonally expanded and harbor an integrated provirus. A persistent tures resulting in a division of the spectrumof the disease into 10,11 oligo/polyclonal expansion of HTLV-1-bearing cells has been four clinical subtypes referred to as acute, lymphoma, shown to precede ATLL, supporting the fact that in ATLL tumor chronic and smoldering subtypes. Infection early in life is cru- cells arise from a clonally expanding non-malignant cell. It is cial in the development of ATLL.12 The prolonged premalig- possible to isolate infected, ie preleukemic, cells during the nant asymptomatic phase that precedes leukemia is charac- premalignant asymptomatic phase of the infection, thus provid- terized by the persistent oligoclonal expansion of HTLV-1 ing an exceptional system to study the mechanisms underlying 13–21 human cancers. Here we review some of the consequences of infected cells. This results fromthe action of the HTLV-1 22,23 HTLV-1 on its host cell in vivo, at different stages of infection. Tax protein that triggers T cell proliferation and negatively Leukemia (2003) 17, 26–38. doi:10.1038/sj.leu.2402777 interferes with the main cellular pathways involved in the Keywords: adult T cell leukemia; HTLV-1; genetic variability; maintenance of genomic integrity.22–30 The mutagenic effect leukemogenesis; mutation of Tax generates a hitherto undescribed mechanism of retro- virus genetic variability that results from somatic mutations of the proviral sequence rather than fromreverse transcription. 18 Introduction In fact, HTLV-1 genetic variability and infected cell genetic instability go hand in hand, thereby establishing a pro- The fact that the DNA of cancer cells is different fromthe cancer genotype. DNA of normal cells indicates that carcinogenesis involves substantial errors in DNA replication, deficits in DNA repair, and alterations in chromosomal segregation.1 Given the rarity Reverse transcription is an error-prone process of mutations in normal cells and the large numbers of mutations observed in human cancers, it has been proposed RNA viruses are unique in that their polymerases, although that the spontaneous mutation rate in normal cells is not suf- clearly marked by the same basic quaternary structure of the ficient to account for the number of mutations found in human polymerization domain common to all nucleic acid poly- tumors. In other words, cancer is assumed to result from an merases, lack a particular domain encoding a 3Ј exonucle- increased somatic mutations frequency, ie from a mutator ase.31,32 Furthermore, host exonucleases are not incorporated phenotype. DNA damage, combined with loss of DNA repair into specific virions. Consequently, any polymerization error and clonal selection, is thought to help move the normal cell becomes immortalized. Not surprisingly, the highest mutation towards such a phenotype. rates observable for microbes are to be found in RNA The main human tumor viruses include human T cell leuke- viruses.33 Higher mutation rates – referred to hypermutations – mia viruses, Epstein–Barr virus, human papilloma virus, can theoretically and practically be encountered. However, Kaposi sarcoma-associated herpes virus and human hepatitis there comes a threshold beyond which the mutation rate is B and C viruses. These virus provide exceptional systems to deleterious to the survival of the virus.33 Retroviruses are study the mechanisms underlying human cancers. Among somewhat schizophrenic: on the one hand they undertake these, human T cell leukemia viruses type 1 (HTLV-1), the first DNA polymerization, while on the other hand their reverse human pathogenic retrovirus isolated, is the etiologic agent of transcriptase is devoid of any 3Ј exonucleolytic activity. Thus the malignant CD4 T lymphoproliferation adult T cell the genetic variability typical of RNA viruses becomes part of their way of life. For some reason that is not yet evident, the average mutation rate of retroviruses is approximately 20-fold Correspondence: E Wattel, Unite´ d’Oncogene`se Virale, UMR5537- lower than that of an ensemble of familiar RNA viruses.34 CNRS-Universite´ Claude Bernard, Centre Le´on Be´rard, 28, rue Lae¨n- nec 69373 Lyon cedex 08 France; Fax: 33 4 78 78 27 17 3 Present address: National Fund for Scientific Research, Faculte´ Univ- HTLV-1 is genetically stable ersitaire des Sciences Agronomiques, Biologie Mole´culaire, 13 avenue Mare´chal Juin, B5030 Gembloux, Belgium 35 The first two authors contributed equally to this work The first complete HTLV-1 sequence emerged in 1983. Received 11 June 2002; accepted 31 July 2002 Since then, a forcible accumulation of sequence data has Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo F Mortreux et al 27 shown that HTLV-1 is extraordinarily stable genetically. While some segments are slightly more variable than others, geo- graphically widely dispersed viruses are <10% divergent at the nucleic acid level. This includes isolates fromtribes and aboriginal populations isolated from the mainstream of human movement for thousands of years.36 Intrapatient variability is usually <0.5%, a value significantly lower than that observed with lentiviruses, such as HIV-1. The intrapatient variation of the HIV-1 envelope protein 5 years post infection is greater than that of all HTLV-1 envelope proteins to date.37 Even anti- genically stable RNA viruses, such as measles and hepatitis A virus, have, in this PCR era, shown more variability than expected. Thus HTLV-1, and its close or distant cousins, HTLV-2 and bovine leukemia virus (BLV) respectively, consti- tute remarkable exceptions, unique among the genetically promiscuous RNA viruses. Figure 1 Schematic representation of HTLV-1 replication in vivo. Highcirculating proviral loads characterizeHTLV-1 infection The non-malignant neurological disorder TSP/HAM is accompanied by very high proviral loads, sometimes approaching 1/5 peripheral blood mononuclear cells.38–43 Consequently, substantial proportions of the CD4 T cells in the periphery may be infected. Proviral loads during the long asymptomatic phase of infection are lower than in TSP/HAM, although they may be as high as 1/25 PBMCs.38–43 Here, there is evidence of an extensive replication, yet HTLV-1 is geneti- cally more stable than any other RNA virus. HIV proviral loads in late-stage disease, AIDS, may reach up to 1/100 to 1/30 in the periphery. In other words HIV-1 also shows signs of exten- sive viral replication, although the maximum HIV-1 proviral load is lower than that observed for HTLV-1. Yet HIV-1 varies considerably, as one would expect.37 By contrast, HTLV-1 remains stable while displaying very high proviral loads. How is this possible? The misincorporation rate of HTLV-1 reverse transcriptase turns out to be on the lower side (7 × 10−6/base/cycle),44,45 while that of HIV-1 is on the upper side (3.5 × 10−5/base/cycle).46 Only one log discriminates between them. Of all the components underlying viral variation, the Figure 2 Distribution of HTLV-1 infected clones in two patients mutation rate is among the least important while the number with TSP/HAM (patients P1 and P2). DNA fromPBMCs was analyzed of successive cycles of replication is probably the most by IPCR. Each signal on the gel corresponds to a cluster of >100 provi- important.47 How can the virus remain stable while rep- ruses with the same flanking sequence, ie belonging to the same cellu- licating intensely? lar clone. Quadruplicate experiments permitted estimation of the abundance of cells within circulating clones, most abundant cells being the most frequently detected after four experiments. M, molecu- lar weight marker; NC, negative control (adapted from Ref. 18). Persistent clonal expansion of infected cells, a way of life for HTLV-1 via mitosis rather than via reverse transcription. Analyzing the The paradoxical combination of an elevated proviral load pattern of HTLV-1 replication over time revealed that the Tax- with a remarkable genetic stability suggested that the virus driven expansion of T cells may persist for considerable per- replicated in concert with cell mitosis (Figure 1).19 This was iods of time, despite strong cellular immunity. Hence, most confirmed for all cases of HTLV-1 infection, notably asympto- circulating HTLV-1-positive clones persist over time. How- matic carriers, TSP/HAM and ATLL.13 In ATLL, tumor cell ever, the abundance of these persistent clones, ie the number clones were identified against a general background of oligo- of cells within clones, is shown to fluctuate over time in some or polyclonal expansion of infected, but non-transformed infected individuals, suggesting that the degree of infected T cells.14 The number of clones detected varied considerably cell proliferation (or elimination) varies over time.
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