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Human Retroviruses in the Second Decade: a Personal Perspective

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Human Retroviruses in the Second Decade: a Personal Perspective © 1995 Nature Publishing Group http://www.nature.com/naturemedicine • REVIEW Human retroviruses in the second decade: A personal perspective Human retroviruses have developed novel strategies for their propagation and survival. A consequence of their success has been the induction of an extraordinarily diverse set of human dlst!ases, including AIDS, cancers and neurological and Inflammatory disorders. Early research focused on their characterization, linkage to these dlst!ases, and the mechanisms Involved. Research should now aim at the eradication of human retroviruses and on treatment of infected people. Retroviruses are transmitted either geneti- .................... ···.. .... ·. ..... .. discovered". Though its characteristics are cally (endogenous form) or as infectious ROBERT C. GALLO strikingly similar to HTLV-1, HTLV-II is not agents (exogenous form)'·'. As do many so clearly linked to human disease. It is cu­ other animal species, humans have both forms ..... In general, rious that HTLV-11 is endemic in some American Indians and endogenous retroviruses are evolutionary relics of old infec­ more prevalent in drug addicts than HTLV-I"·'•. tions and are not known to cause disease. The DNA of many HIV-1 is also most prevalent in equatorial Africa, but in con­ species, including humans, harbours multiple copies of differ­ trast to HTLV the demography of the HIV epidemic is still in ent retroviral proviruses. The human endogenous proviral flux, and the virus is new to most of the world. The number of sequences are virtually all defective, and comprise about one infected people worldwide is now estimated to be about 17 mil­ percent of the human genome, though R. Kurth's group in lion and is predicted to reach 30 to SO million by the year 2000. Frankfurt showed that one, called HERV-K, can code for all typ­ However, precise predictions are not possible because of varying ical retroviral gene products and form particles•. Future interest human behaviour and cofactors for transmission. The far greater in these sequences will depend on demonstrating some func­ variability of HIV as compared with HTLV also leaves open the tion or role in disease. possibility of emergence of variants with greater sexual trans­ The infectious retroviruses are, of course, another story. In hu­ missibility, as suggested by Max Essex (pers. commun.). mans they may directly cause leukaemias, neurological diseases, Both the HTL Vs and HIVs have counterparts in Old World inflammatory disorders and immune deficiency, as well as en­ monkeys known as simian T-cell leukaemia virus type I (STLV- hancing the incidence of other cancers (including B-cell 1), and simian immunodeficiency virus (SIV), respectively. As a lymphoma, cancer of the liver, and cervical cancer, indirectly, result, studies of human retroviruses in these animals have presumably by fostering replication of other viruses. There are been of interest". two groups of infectious human retroviruses: the human T-cell In vitro as well as in vivo the most dramatic effects of both leukaemia/lymphotropic viruses (HTLV-1 and HTLV-11) belonging HTLVs and HIVs are seen on the CD4' T cell. Although HTLV to the oncoretroviridae and the human immunodeficiency infects several T-cell subtypes (its receptor remains unknown), viruses (HIV-1 and HIV-2) belonging to the lentiretroviridae'·''. In it chiefly immortalizes the CD4' T cell which is the same cell this review, HTLV refers to HTLV-1; likewise, HIV refers to HIV-1. type to develop leukaemia. The major receptor.for HIV is CD4. Consequently, HIVs infect chiefly the CD4+ T cell and cells of Similarities and contrasts the monocyte/macrophage lineage that also express CD4. As do all retroviruses, human retroviruses replicate through a Other cell types may be infected, perhaps mediated by Fe or DNA intermediate (the provirus), which integrates in the target complement receptors in the presence of antiviral antibodies. cell DNA where it may remain transcriptionally silent. In fact, In contrast to HTLV-1, HIV is cytopathic for CD4' T cells often latency may be the chief means by which the HTLVs escape im­ inducing massive syncytia formation and abruptly killing the 17 mune detection. HIV infections are, however, often not latent. infected cell after the cell is activated • A difference between Their survival also involves chronic high-level replication and the two groups of human retroviruses is the relative ease of steady destruction of the immune system. The routes of trans­ transmission by HIV as cell-free virions compared with the mission of HTLV-1, the first discovered human retrovirus'·", HTLVs, which are probably only transmitted by infected cells. were shown to be through sex, from mother to child and via This difference may account for the more rapid spread of HIV. contaminated blood, similar to the routes later shown for HIV- Both HTL Vs and HIVs take years from the time of infection 1. HTL V-1 is endemic in many parts of the world, including to clinical disease, but for HIV there is no real latency. From in equatorial Africa, southern japan, Central and South America, situ studies in 1985 we have known some infected cells are al­ and in the immigrant descendants of people from these regions. ways expressing virus, and more recently we have learned that Recent molecular epidemiological studies revealed several sub­ there is much more ongoing HIV-1 replication and cell killing types, a prevalent type called 'cosmopolitan' HTLV-1 and other than previously thought to occur••. .., especially in lymph 21 subtypes endemic in parts of the South Pacific and equatorial nodes"'· • Africa" . Although distinguishing these isolated subtypes of HTLV-I may be only of academic interest, it remains possible HTLV as a cause of leukaemia that they may cause unexpected diseases. A year after the dis­ HTLV-I was established as the cause of an aggressive adult T-cell covery of HTLV-1, a second human retrovirus, HTLV-II, was leukaemia (ATL) in 1980-81 (refs 10- 12, 22, 23), just before NATURE MEDICINE, VOLUME I, NUMBER 8, AUGUST 1995 753 © 1995 Nature Publishing Group http://www.nature.com/naturemedicine ········•····· ···· ··· ·· ····· ·· ···· ··· ······ ··· REVIEW detection of the first cases of AIDS. About two to five per cent velop as a result of Tax activation of cytokines in T cells infil­ of infected people per 70-year life span develop leukaemia. A trating specific tissue sites, autoimmune phenomena, other similar number may develop serious neurological or inflamma­ disturbances of the immune system or some other mechanism tory disease. It has recently been suggested that leukaemia is unknown and, as forMS, the ultimate importance of HTLV develops in individuals infected in infancy by .maternal trans­ in these illnesses may be in elucidating molecular mechanisms mission, in contrast to the neurological disorders, which are for their more common (non-HTLV associated) forms. more apt to occur following adult infection by sexual transmis­ sion><. Because HTLVs immortalize some infected T cells and Therapy and prevention of HTLV-1 disease because the Tax protein transactivates not only HTL V-1 genes Adult T-cell leukaemia is not curable despite extensive infor­ but several cellular genes, including interleukin-2 (IL-2) and the mation on its cause and pathogenesis and on the properties of alpha chain of the IL-2 receptor (IL-2Ra.), Tax has been invoked the leukaemic cell. Most therapy is based on combination cyto­ 25 2 as the key to the events leading toT-cell immortalization • " . toxic chemotherapy, although Waldmann and colleagues have However, because IL-2 production is only transient, other pioneered a rational approach to delivering cell-killing radionu­ events must be involved in the eventuallL-2 independent T­ cleotides selectively to the ATL cell by targeting their ee!! proliferation. A candidate mechanism involves a newly constitutively expressed 1L-2Ra. chainJO. Others have used a com­ discovered HTLV-1 protein, pl2', which binds to the beta chain bination of azidothymidine (AZT) and interferon alpha (lFN-a.), 2 of the IL-2R in the cytoplasmic domain of a region connected presumably as antiviral agents"·' • Remission of the leukaemia to a signal transduction pathwayn. This and other newly found occurred in most patients. However, after development of ATL, HTL V proteins are products of messenger RNA (mRNA) formed HTLV-1 replication is not needed to maintain the leukaemia. by using different splice sites from the major mRNA. Tax also Although the logic of this approach might be faulted, the results transactivates genes for many other cytokines and HLA. so far cannot be. AZT and IFN-a. not only interfere with virus Although it is not easy to speculate on the overall effects of the replication, they also affect cell metabolism. It will be of impor­ activation of a large number of cytokines by Tax, one, lL-7, also tance to elucidate their synergistic effects on ATL cells. promotes T-ee!! proliferation utilizing the gamma chain of the The legacy of HTLV-1 will not only be as the retrovirus forerun­ IL-2R. Other effects of Tax may lead to genetic diversity of in­ ner of HIV. In the 15-16 years since its discovery, practical public fected cells, and some of these changes may promote greater health and clinical therapeutic advances have come out of studies cell proliferation and consequently a greater chance for neo­ of its basic virology. Japan has eliminated or reduced breast feed­ 27 plastic transformation • Slowly, the events leading to T-ee!! ing in HTLV-1 endemic regions, and a blood test for HTLV-1 is immortalization are being elucidated, but immortalization or required in both the United States and Japan for blood donors to even transformation of a cell is not equivalent to development assure safety of the blood supply. These practices should substan­ of leukaemia, which undoubtedly requires further genetic tially reduce HTLV-1 infection.
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