HIV: Antiviral Chemotherapy

  • Samuel Broder

Abstract

The term retrovirus is used to denote a class of animal and human viruses that employ a special DNA polymerase (reverse transcriptase) to catalyze the conversion of genomic RNA to DNA in the process of viral replication. These viruses are interesting in that a crucial step in their replication is the reverse transcription of viral RNA to produce linear, double-stranded (minus strand and plus strand) proviral DNA. In this process the termini of the RNA genome are duplicated to yield structures in the DNA called long-terminal repeats (LTRs). The viral genome is expressed from proviral DNA (the minus strand of DNA), which has enhancer/promoter and polyadenylation signals in the LTRs.

Keywords

Lymphoma Dementia Sarcoma Interferon Enzymatic Degradation 

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References

  1. 1.
    Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Daughet C, Axler-Blin C, Vezinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L (1983) Isolation of a T cell lymphotropic virus from a patient at risk for acquired immunodeficiency syndrome ( AIDS ). Science 220: 868–871PubMedCrossRefGoogle Scholar
  2. 2.
    Popovic M, Sarngadharan MG, Read E, Gallo RC (1984) Detection, isolation, and continuous production of cytopathic retrovirus ( HTLV-III) from patients with AIDS and pre-AIDS. Science 224: 497–500PubMedCrossRefGoogle Scholar
  3. 3.
    Miller R (1988) Human immunodeficiency virus may encode a novel protein on the genomic DNA plus strand. Science 239: 1420–1422PubMedCrossRefGoogle Scholar
  4. 4.
    Mitsuya H, Broder S (1987) Strategies of antiviral therapy in AIDS. Nature 325: 773–778PubMedCrossRefGoogle Scholar
  5. 5.
    Mitsuya H, Broder S (1986) Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy associated virus (HTLV-III/LAV) by 2’,3’-dideoxynucleosides. Proc Natl Acad Sci USA 83: 1911–1915PubMedCrossRefGoogle Scholar
  6. 6.
    Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S (1985) 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 USA 82: 7096–7100PubMedCrossRefGoogle Scholar
  7. 7.
    Yarchoan R, Klecker RW, Weinhold KJ, Markham PD, Lyerly HK, Durack DT, Gelmann E, Lehrman SN, Blum RM, Barry DW, Shearer GM, Fischi MA, Mitsuya H, Gallo RC, Collins JM, Bolognesi DP, Myers CE, Broder S (1986) Administration of 3’-azido-3’-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet i: 575–580Google Scholar
  8. 8.
    Fischl M, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Allan JD, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D, AZT Collaborative Working Group (1987) The efficacy of 3’-azido-3’deoxythymidine (azidothymidine) in the treatment of patients with AIDS and AIDS-related complex: A double-blind placebo-controlled trial. New Engl J Med 317: 185–191PubMedCrossRefGoogle Scholar
  9. 9.
    Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A (1981) Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men. Evidence of a new acquired cellular immunodeficiency. New Engl J Med 305: 1425–1431PubMedCrossRefGoogle Scholar
  10. 10.
    Snider WD, Simpson DM, Nielsen S, Gold JWM, Metroka CE, Posner JB (1983) Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients. Ann Neurol 14: 403–418PubMedCrossRefGoogle Scholar
  11. 11.
    Shaw GM, Harper ME, Epstein LG, Gajdusek DC, Price RW, Navia BA, Petito CK, O’Hara CJ, Groopman JE, Cho ES, Oleske JM, Wong-Staal F, Gallo RC (1985) HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science 227: 177–182PubMedCrossRefGoogle Scholar
  12. 12.
    Yarchoan R, Berg G, Brouwers P, Spitzer AR, Fischl MA, Thomas RV, Schmidt P, Safai B, Perno CF, Myers CE, Broder S (1987) Preliminary observation of the response of HTLV-III/LAV-associated neurological disease to the administration of 3’-azido-3’-deoxythymidine. Lancet i: 132–135Google Scholar
  13. 13.
    Mitsuya H, Matsukura M, Broder S (1987) Rapid in vitro systems for assessing activity of agents against HTLV-III/LAV. In Broder S (ed) AIDS: Modern Concepts and Therapeutic Challenges. Marcel Dekker, New York, pp 303–333Google Scholar
  14. 14.
    Baltimore D (1970) Viral RNA-dependent DNA polymerase. Nature 226: 1209–1211PubMedCrossRefGoogle Scholar
  15. 15.
    Temin HM, Mizutani S (1970) RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 226: 1211–1213PubMedCrossRefGoogle Scholar
  16. 16.
    Strebel K, Daugherty D, Clouse K, Cohen D, Folks T, Martin MA (1987) The HIV ‘A’ (sor) gene product is essential for virus infectivity. Nature 328: 728–730PubMedCrossRefGoogle Scholar
  17. 17.
    Guy B, Kieny MP, Riviere Y, Peuch CL, Dott K, Girard M, Montagnier L, Lecocq JP (1987) HIV F/3’-orf encodes a phosphorylated GTP-binding protein resembling an oncogene product. Nature 330: 266–269PubMedCrossRefGoogle Scholar
  18. 18.
    Smith DH, Byrn RA, Marsters SA, Gregory T, Groopman JE, Capon DJ (1987) Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science 228: 1704–1707CrossRefGoogle Scholar
  19. 19.
    Fisher AG, Ratner L, Mitsuya H, Marselle LM, Harper ME, Broder S, Gallo RC, Wong-Staal F (1986) Infectious mutants of HTLV-III with changes in the 3’-orf region and markedly reduced cytopathic effects. Science 233: 655–659PubMedCrossRefGoogle Scholar
  20. 20.
    Matsushita S, Robert-Guroff M, Trepel J, Cossman J, Mitsuya H, Broder S (1986) Human monoclonal antibody directed against an envelope glycoprotein of human T-cell leukemia virus type I. Proc Natl Acad Sci USA 93: 2672–2676CrossRefGoogle Scholar
  21. 21.
    Nabel G, Rice S, Knipe D, Baltimore D (1988) Alternative mechanisms for activation of human immunodeficiency virus enhancer in T cells. Science 239: 1299–1301PubMedCrossRefGoogle Scholar
  22. 22.
    Felber B, Pavlakis G (1988) A quantitative bioassay for HIV-I based on transactivation. Science 238: 184–187CrossRefGoogle Scholar
  23. 23.
    Sodroski J, Rosen C, Wong-Staal F, Salahuddin SZ, Popovic M, Arya S, Gallo RC (1985) Transacting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat. Science 227: 171–173PubMedCrossRefGoogle Scholar
  24. 24.
    Sodroski J, Goh WC, Rosen C, Dayton A, Terwilliger E, Haseltine WA (1986) A second post-transcriptional transactivator gene required for HTLV-III replication. Nature 321: 412–417PubMedCrossRefGoogle Scholar
  25. 25.
    Feinberg MB, Jarrett RF, Aldovini A, Gallo RC, Wong-Staal F (1986) HTLV-III expression and production involve complex regulation at the level of splicing and translation of viral RNA. Cell 46: 807–817PubMedCrossRefGoogle Scholar
  26. 26.
    McCormick JB, Getchell JP, Mitchell SW, Hicks DR (1984) Ribavirin suppresses replication of lymphadenopathy-associated virus in culture of human adult lymphocytes. Lancet ii: 1367–1369Google Scholar
  27. 27.
    Matsukura M, Shinozuka K, Zon G, Mitsuya H, Reitz M, Cohen JS, Broder S (1987) Phosphorothioate analogs of ologodeoxynucleotides: Inhibition of replication and cytopathic effects of human immunodeficiency virus. Proc Natl Acad Sci USA 84: 7706–7710PubMedCrossRefGoogle Scholar
  28. 28.
    Gruters RA, Neefjes JJ, Tersmette M, Goede RY, Tulp A, Huisman HG, Miedema F, Ploegh HL (1987) Interference with HIV-induced syncytium formation and viral infectivity by inhibitors of trimming glucosidase. Nature 330: 74–77PubMedCrossRefGoogle Scholar
  29. 29.
    Montefiori DC, Mitchell WM (1987) Antiviral activity of mismatched double-stranded RNA against human immunodeficiency virus in vitro. Proc Natl Acad Sci USA 84: 2985–2989PubMedCrossRefGoogle Scholar
  30. 30.
    Baba M, Pauwels R, Herdewijn P, De Clercq E, Desmyter J, Vandeputte M (1987) Both 2’-3’-dideoxythymidine and its 2’-3’-unsaturated derivative (2’-3’-dideoxythumidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem Biophys Res Commun 142: 128–134PubMedCrossRefGoogle Scholar
  31. 31.
    Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groompan JE, Mildvan D, Hirsch MS, Jackson GG, Durack DT, Lehrman SN, AZT Collaborative Working Group (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. New Engl J Med 317: 192–197PubMedCrossRefGoogle Scholar
  32. 32.
    Yarchoan R, Perno CF, Thomas RV, Klecker RW, Allain JP, Willis RJ, McAtee N, Fischl MA, Dubinsky R, McNeely MC, Mitsuya H, Pluda JM, Lawley TJ, Leuther M, Safai B, Collins JM, Meyers CE, Broder S (1988) Phase I studies of 2’-3’-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with Zidovudine (AZT). Lancet i: 76–81Google Scholar
  33. 33.
    Mitsuya H, Jarrett RF, Matsukura M, DiMarzo Veronese F, DeVico AL, Sarngadharan MG, Johns DG, Reitz MS, Broder S (1987) Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2’-3’-dideoxynucleosides in vitro. Proc Natl Acad Sci USA 84: 2033–2037PubMedCrossRefGoogle Scholar
  34. 34.
    Dahlberg JE, Mitsuya H, Broder S, Blam SB, Aaronson SA (1987) Broad spectrum anti-retroviral activity of 2’-3’-dideoxynucleosides. Proc Natl Acad Sci USA 84: 2469–2473PubMedCrossRefGoogle Scholar
  35. 35.
    Larder BA, Purifoy JM, Powell KL, Darby G (1987) Site-specific mutagenesis of AIDS virus reverse trnascriptase. Nature 327: 716–717PubMedCrossRefGoogle Scholar
  36. 36.
    Balzarini J, Pauwells R, Baba M, Herdewijn P, de Clercq E, Broder S, Johns DG (1988) The in vitro and in vivo anti-retrovirus activity, and intracellular metabolism of 3 ’-azido-2’-3’-dideoxythymidine and 2’-3’-dideoxycytidine are highly dependent on the cell species. Biochem Pharm 37: 897–903PubMedCrossRefGoogle Scholar
  37. 37.
    Ostertag W, Roesler G, Krieg CJ, Kind J, Cole T, Crozier T, Gaedicke G, Steinheider G, Kluge N, Dube S (1974) Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus. Proc Natl Acad Sci USA 71: 4980–4985PubMedCrossRefGoogle Scholar
  38. 38.
    De Wolfe F, Lange JMA, Goudsmit J, Cload P, De Gans J, Schellekens PTH (1988) Effect of Zidovudine on serum human immunodeficiency virus antigen levels in symptom-free subjects. Lancet 1: 373–376CrossRefGoogle Scholar
  39. 39.
    Moss A, Bacchetti P, Osmond D, Krampf W, Chaisson R, Stites D, Wilber J, Allain J, Carlson J (1988) Seropositivity for HIV and development of AIDS or AIDS-related condition: Three year follow-up of the San Francisco General Hospital cohort. Br Med J, 745–750Google Scholar

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© Springer-Verlag New York Inc. 1989

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  • Samuel Broder

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