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. 1986 Mar;83(6):1911–1915. doi: 10.1073/pnas.83.6.1911

Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides.

H Mitsuya, S Broder
PMCID: PMC323194  PMID: 3006077

Abstract

Human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-associated virus (LAV) is a a newly discovered lymphotropic retrovirus that is cytopathic for helper/inducer T cells in vitro. This virus is the etiologic agent of the acquired immunodeficiency syndrome and related diseases. In the current study, we tested the capacity of purine and pyrimidine nucleoside derivatives to inhibit the infectivity and cytopathic effect of human T-lymphotropic virus type III in vitro. With the ribose moiety of the molecule in a 2',3'-dideoxy configuration, every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside tested suppressed the virus, although the thymidine derivative seemed to have substantially less activity in our system than the others. In general, we observed essentially complete suppression of the virus at doses that were lower by a factor of 10 to 20 than those needed to inhibit the proliferation of the target T cells and the immune reactivity of normal T cells in vitro. An analysis of five adenosine congeners, which differed only in the sugar moiety, revealed that reduction (an absence of hydroxyl determinants) at both the 2' and 3' carbons of the ribose was necessary for an anti-viral effect, and an additional reduction at the 5' carbon nullified the anti-viral activity. These observations may be of value in developing a new class of experimental drugs for the therapy of human T-lymphotropic virus type III infections.

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Selected References

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  1. Atkinson M. R., Deutscher M. P., Kornberg A., Russell A. F., Moffatt J. G. Enzymatic synthesis of deoxyribonucleic acid. XXXIV. Termination of chain growth by a 2',3'-dideoxyribonucleotide. Biochemistry. 1969 Dec;8(12):4897–4904. doi: 10.1021/bi00840a037. [DOI] [PubMed] [Google Scholar]
  2. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  3. Broder S., Gallo R. C. A pathogenic retrovirus (HTLV-III) linked to AIDS. N Engl J Med. 1984 Nov 15;311(20):1292–1297. doi: 10.1056/NEJM198411153112006. [DOI] [PubMed] [Google Scholar]
  4. Brun-Vézinet F., Rouzioux C., Montagnier L., Chamaret S., Gruest J., Barré-Sinoussi F., Geroldi D., Chermann J. C., McCormick J., Mitchell S. Prevalence of antibodies to lymphadenopathy-associated retrovirus in African patients with AIDS. Science. 1984 Oct 26;226(4673):453–456. doi: 10.1126/science.6238406. [DOI] [PubMed] [Google Scholar]
  5. Ciarrocchi G., Jose J. G., Linn S. Further characterization of a cell-free system for measuring replicative and repair DNA synthesis with cultured human fibroblasts and evidence for the involvement of DNA polymerase alpha in DNA repair. Nucleic Acids Res. 1979 Nov 10;7(5):1205–1219. doi: 10.1093/nar/7.5.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Edenberg H. J., Anderson S., DePamphilis M. L. Involvement of DNA polymerase alpha in simian virus 40 DNA replication. J Biol Chem. 1978 May 10;253(9):3273–3280. [PubMed] [Google Scholar]
  7. Faras A. J., Taylor J. M., Levinson W. E., Goodman H. M., Bishop J. M. RNA-directed DNA polymerase of Rous sarcoma virus: initiation of synthesis with 70 S viral RNA as template. J Mol Biol. 1973 Sep 5;79(1):163–183. doi: 10.1016/0022-2836(73)90277-5. [DOI] [PubMed] [Google Scholar]
  8. Feorino P. M., Jaffe H. W., Palmer E., Peterman T. A., Francis D. P., Kalyanaraman V. S., Weinstein R. A., Stoneburner R. L., Alexander W. J., Raevsky C. Transfusion-associated acquired immunodeficiency syndrome. Evidence for persistent infection in blood donors. N Engl J Med. 1985 May 16;312(20):1293–1296. doi: 10.1056/NEJM198505163122005. [DOI] [PubMed] [Google Scholar]
  9. Furmanski P., Bourguignon G. J., Bolles C. S., Corombos J. D., Das M. R. Inhibition by 2',3'-dideoxythymidine of retroviral infection of mouse and human cells. Cancer Lett. 1980 Feb;8(4):307–315. doi: 10.1016/0304-3835(80)90146-9. [DOI] [PubMed] [Google Scholar]
  10. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  11. Ho D. D., Hartshorn K. L., Rota T. R., Andrews C. A., Kaplan J. C., Schooley R. T., Hirsch M. S. Recombinant human interferon alfa-A suppresses HTLV-III replication in vitro. Lancet. 1985 Mar 16;1(8429):602–604. doi: 10.1016/s0140-6736(85)92144-0. [DOI] [PubMed] [Google Scholar]
  12. Klatzmann D., Barré-Sinoussi F., Nugeyre M. T., Danquet C., Vilmer E., Griscelli C., Brun-Veziret F., Rouzioux C., Gluckman J. C., Chermann J. C. Selective tropism of lymphadenopathy associated virus (LAV) for helper-inducer T lymphocytes. Science. 1984 Jul 6;225(4657):59–63. doi: 10.1126/science.6328660. [DOI] [PubMed] [Google Scholar]
  13. Krokan H., Schaffer P., DePamphilis M. L. Involvement of eucaryotic deoxyribonucleic acid polymerases alpha and gamma in the replication of cellular and viral deoxyribonucleic acid. Biochemistry. 1979 Oct 2;18(20):4431–4443. doi: 10.1021/bi00587a025. [DOI] [PubMed] [Google Scholar]
  14. McCormick J. B., Getchell J. P., Mitchell S. W., Hicks D. R. Ribavirin suppresses replication of lymphadenopathy-associated virus in cultures of human adult T lymphocytes. Lancet. 1984 Dec 15;2(8416):1367–1369. doi: 10.1016/s0140-6736(84)92060-9. [DOI] [PubMed] [Google Scholar]
  15. Miller M. R., Chinault D. N. Evidence that DNA polymerases alpha and beta participate differentially in DNA repair synthesis induced by different agents. J Biol Chem. 1982 Jan 10;257(1):46–49. [PubMed] [Google Scholar]
  16. Mitsuya H., Guo H. G., Cossman J., Megson M., Reitz M. S., Jr, Broder S. Functional properties of antigen-specific T cells infected by human T-cell leukemia-lymphoma virus (HTLV-I). Science. 1984 Sep 28;225(4669):1484–1486. doi: 10.1126/science.6206569. [DOI] [PubMed] [Google Scholar]
  17. Mitsuya H., Matsushita S., Harper M. E., Broder S. Pharmacological inhibition of infectivity of HTLV-III in vitro. Cancer Res. 1985 Sep;45(9 Suppl):4583s–4587s. [PubMed] [Google Scholar]
  18. Mitsuya H., Popovic M., Yarchoan R., Matsushita S., Gallo R. C., Broder S. Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science. 1984 Oct 12;226(4671):172–174. doi: 10.1126/science.6091268. [DOI] [PubMed] [Google Scholar]
  19. Mitsuya H., Weinhold K. J., Furman P. A., St Clair M. H., Lehrman S. N., Gallo R. C., Bolognesi D., Barry D. W., Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ono K., Ogasawara M., Matsukage A. Inhibition of the activity of DNA polymerase alpha by 2',3'-dideoxythymidine 5'-triphosphate. Biochem Biophys Res Commun. 1979 Jun 27;88(4):1255–1262. doi: 10.1016/0006-291x(79)91115-x. [DOI] [PubMed] [Google Scholar]
  21. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  22. Rozenbaum W., Dormont D., Spire B., Vilmer E., Gentilini M., Griscelli C., Montagnier L., Barre-Sinoussi F., Chermann J. C. Antimoniotungstate (HPA 23) treatment of three patients with AIDS and one with prodrome. Lancet. 1985 Feb 23;1(8426):450–451. doi: 10.1016/s0140-6736(85)91162-6. [DOI] [PubMed] [Google Scholar]
  23. Sandstrom E. G., Kaplan J. C., Byington R. E., Hirsch M. S. Inhibition of human T-cell lymphotropic virus type III in vitro by phosphonoformate. Lancet. 1985 Jun 29;1(8444):1480–1482. doi: 10.1016/s0140-6736(85)92255-x. [DOI] [PubMed] [Google Scholar]
  24. Sarngadharan M. G., Popovic M., Bruch L., Schüpbach J., Gallo R. C. Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS. Science. 1984 May 4;224(4648):506–508. doi: 10.1126/science.6324345. [DOI] [PubMed] [Google Scholar]
  25. Schüpbach J., Popovic M., Gilden R. V., Gonda M. A., Sarngadharan M. G., Gallo R. C. Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDS. Science. 1984 May 4;224(4648):503–505. doi: 10.1126/science.6200937. [DOI] [PubMed] [Google Scholar]
  26. Shaw G. M., Harper M. E., Hahn B. H., Epstein L. G., Gajdusek D. C., Price R. W., Navia B. A., Petito C. K., O'Hara C. J., Groopman J. E. HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science. 1985 Jan 11;227(4683):177–182. doi: 10.1126/science.2981429. [DOI] [PubMed] [Google Scholar]
  27. Smoler D., Molineux I., Baltimore D. Direction of polymerization by the avian myeloblastosis virus deoxyribonucleic acid polymerase. J Biol Chem. 1971 Dec 25;246(24):7697–7700. [PubMed] [Google Scholar]
  28. Snider W. D., Simpson D. M., Nielsen S., Gold J. W., Metroka C. E., Posner J. B. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol. 1983 Oct;14(4):403–418. doi: 10.1002/ana.410140404. [DOI] [PubMed] [Google Scholar]
  29. Waqar M. A., Evans M. J., Huberman J. A. Effect of 2',3'-dideoxythymidine-5'-triphosphate on HeLa cell in vitro DNA synthesis: evidence that DNA polymerase alpha is the only polymerase required for cellular DNA replication. Nucleic Acids Res. 1978 Jun;5(6):1933–1946. doi: 10.1093/nar/5.6.1933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Waqar M. A., Evans M. J., Manly K. F., Hughes R. G., Huberman J. A. Effects of 2',3'-dideoxynucleosides on mammalian cells and viruses. J Cell Physiol. 1984 Nov;121(2):402–408. doi: 10.1002/jcp.1041210218. [DOI] [PubMed] [Google Scholar]
  31. di Marzo Veronese F., Sarngadharan M. G., Rahman R., Markham P. D., Popovic M., Bodner A. J., Gallo R. C. Monoclonal antibodies specific for p24, the major core protein of human T-cell leukemia virus type III. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5199–5202. doi: 10.1073/pnas.82.15.5199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. van der Vliet P. C., Kwant M. M. Role of DNA polymerase gamma in adenovirus DNA replication. Mechanism of inhibition by 2',3'-dideoxynucleoside 5'-triphosphates. Biochemistry. 1981 Apr 28;20(9):2628–2632. doi: 10.1021/bi00512a041. [DOI] [PubMed] [Google Scholar]

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