Abstract
The retroviruses human T-cell lymphotrophic virus-I (HTLV-I)1,2 and HTLV-III/LAV (lymphadenopathy-associated virus)3,4 are clearly linked to human diseases. Patients with HTLV-I-positive neoplasms may respond transiently to traditional chemotherapy, but are not cured5. For patients with acquired immune deficiency syndrome (AIDS) there is no curative therapy6. In retroviruses of different species, viral propagation crucially depends on reverse transcriptase, an enzyme not present in normal mammalian cells and different from mammalian DNA polymerases, making it a target for specific inhibition. Reverse transcriptase has been well conserved through evolution: an LAV isolate contained a 250-amino-acid-long domain, presumably the reverse transcriptase core sequence, which has 21% homology to Moloney murine leukaemia virus (MoMLV)7. Because HTLV-IH infects only humans and chimpanzees8, we substituted murine retroviruses for in vivo evaluation of candidate anti-AIDS drugs after ascertaining similar inhibition in vitro of HTLV-III and MLVs, which were chosen for their short incubation time. The triphosphate of 3'-azido-3'-deoxythymidine (AZT)9–11 is incorporated into complementary DNA by retroviral reverse transcriptase, causing premature chain termination. Here we show that chronic AZT treatment of mice infected with Rauscher murine leukaemia virus complex (RLV) prevents infection of splenocytes and development of splenomegaly, and suppresses viraemia if started soon after inoculation. Starting AZT late in the course of disease still leads to significant prolongation of life; anaemia, however is a significant side-effect. By analogy, AZT may have a role in preventing retroviral disease in humans if started early after infection, and it may lead to significant survival gains even if started later in the course of disease.
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References
Poiesz, B. J. et al. Proc. natn. Acad. Sci. U.S.A. 77, 7415–7419 (1980).
Yoshida, M., Miyoshi, I. & Hinuma, Y. Proc. natn. Acad. Sci. U.S.A. 79, 2031–2035 (1982).
Popovic, M., Sarngadharan, M. G., Read, E. & Gallo, R. C. Science 224, 497–500 (1984).
Barré-Sinoussi, F. et al. Science 220, 868–871 (1983).
Bunn, P. A., Jr. et al. N. Engl. J. Med. 309, 257–264 (1983).
Curran, J. W. et al. Science 229, 1352–1357 (1985).
Wain-Hobson, S., Sonigo, P., Danos, O., Cole, S. & Alizon, M. Cell 40, 9–17 (1985).
Alter, H. J. et al. Science 226, 549 (1984).
Horwitz, J. P., Chua, J. & Noel, M. J. org. Chem. 29, 2076–2078 (1964).
Lin, T.-S. & Prusoff, W. H. J. med. Chem. 21, 109–112 (1978).
Mitsuya, H. et al. Proc. natn. Acad. Sci. U.S.A. 82, 7096–7100 (1985).
Yarchoan, R. et al. Lancet i, 575–580 (1986).
Rauscher, F. J. J. natn. Cancer Inst. 29, 515–543 (1962).
Steeves, R. A., Strand, M. & August, J. T. J. Virol 14, 187–189 (1974).
Chirigos, M. A. Cancer Res. 24, 1035–1041 (1964).
Ruprecht, R. M., Rossoni, L. D., Haseltine, W. A. & Broder, S. Proc. natn. Acad. Sci. U.S.A. 82, 7733–7737 (1985).
Rowe, W. P., Pugh, W. E. & Hartley, J. W. Virology 42, 1136–1139 (1970).
Pedersen, F. S., Crowther, R. L., Tenney, D. Y., Reimold, A. M. & Haseltine, W. A. Nature 292, 167–170 (1981).
Hartley, J. A. & Rowe, W. P. Virology 65, 128–134 (1975).
Franchini, G., Wong-Staal, F. & Gallo, R. C. Proc. natn. Acad. Sci. U.S.A. 81, 6207–6211 (1984).
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Ruprecht, R., O'Brien, L., Rossoni, L. et al. Suppression of mouse viraemia and retroviral disease by 3′-azido-3′-deoxythymidine . Nature 323, 467–469 (1986). https://doi.org/10.1038/323467a0
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DOI: https://doi.org/10.1038/323467a0
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