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Twenty years of therapy for HIV-1 infection

Nature Medicine volume 9, pages 867–873 (2003)Cite this article

Abstract

Antiretroviral therapy, where available, has transformed HIV-1 disease into a treatable and somewhat chronic infection. This article summarizes the accomplishments thus far and what lies ahead in our struggle to improve the treatment of, and possibly eliminate, HIV-1 infection.

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Figure 1: HIV-1 life cycle.

Katie Ris

Figure 2: NRTIs and NNRTIs: mechanisms of action.

Katie Ris

Figure 3: Protease inhibitors: mechanisms of action.

Katie Ris

Figure 4: Fusion inhibitors: mechanisms of action.

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References

  1. Rothenberg, R. et al. Survival with the acquired immunodeficiency syndrome. Experience with 5833 cases in New York City. N. Engl. J. Med. 317, 1297–1302 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. Pneumocystis pneumonia—Los Angeles. MMWR Morb. Mortal. Wkly. Rep. 30, 250–252 (1981).

  3. Barre-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).

    Article  CAS  PubMed  Google Scholar 

  4. Gallo, R.C. et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 220, 865–867 (1983).

    Article  CAS  PubMed  Google Scholar 

  5. Silberner, J. AIDS blood screen approved. Sci. News 127, 148 (1985).

    Article  PubMed  Google Scholar 

  6. Ezzell, C. AIDS drug gets green light. Nature 329, 751 (1987).

    Article  CAS  PubMed  Google Scholar 

  7. Furman, P.A. & Barry, D.W. Spectrum of antiviral activity and mechanism of action of zidovudine. An overview. Am. J. Med. 85, 176–181 (1988).

    CAS  PubMed  Google Scholar 

  8. Richman, D.D. HIV chemotherapy. Nature 410, 995–1001 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Gershon, D. Green light for ddI. Nature 353, 589 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Concorde Coordinating Committee. Lancet 343, 871–881 (1994).

  11. Volberding, P.A. et al. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. AIDS Clinical Trials Group. N. Engl. J. Med. 333, 401–407 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Update: Mortality attributable to HIV infection among persons aged 25-44 years—United States, 1994. MMWR Morb. Mortal. Wkly. Rep. 45, 121–125 (1996).

  13. Connor, E.M. et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N. Engl. J. Med. 331, 1173–1180 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Venaud, S. et al. Inhibition of HIV by an anti-HIV protease synthetic peptide blocks an early step of viral replication. Res. Virol. 143, 311–319 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Dorsey, B.D. et al. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J. Med. Chem. 37, 3443–3451 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Vacca, J.P. et al. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc. Natl. Acad. Sci. USA 91, 4096–4100 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hammer, S.M. et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N. Engl. J. Med. 337, 725–733 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Hirsch, M. et al. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy. J. Infect. Dis. 180, 659–665 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Gulick, R.M. et al. 3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine. Ann. Intern. Med. 133, 35–39 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Sterling, T.R., Chaisson, R.E. & Moore, R.D. Initiation of highly active antiretroviral therapy ar CD4+ T Lymphocyte counts of >350 cells/mm3: disease progression, treatment durability, and drug toxicity. Clin. Infect. Dis. 36, 812–815 (2003)

    Article  PubMed  Google Scholar 

  21. Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Nolte, F.S. Impact of viral load testing on patient care. Arch. Pathol. Lab. Med. 123, 1011–1014 (1999).

    CAS  PubMed  Google Scholar 

  24. Mellors, J.W. et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann. Intern. Med. 126, 946–954 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Staszewski, S. et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N. Engl. J. Med. 341, 1865–1873 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Saag, M.S. et al. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group. N. Engl. J. Med. 329, 1065–1072 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. DAIDS, N. Trizivir compared to efavirenz plus combivir: 48 weeks interim study results from ACTG 5095. (Center for Disease Control and Prevention, Atlanta, 2003).

  28. Carr, A., Miller, J., Law, M. & Cooper, D.A. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 14, F25–F32 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Carr, A. et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 353, 2093–2099 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Safrin, S. & Grunfeld, C. Fat distribution and metabolic changes in patients with HIV infection. AIDS 13, 2493–2505 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Carr, A. et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 12, F51–F58 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Bangsberg, D.R. et al. Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS 15, 1181–1183 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Bangsberg, D.R. et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS 14, 357–366 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Young, B. et al. Open-label study of a twice-daily indinavir 800-mg/ritonavir 100-mg regimen in protease inhibitor-naive HIV-infected adults. J. Acquir. Immune Defic. Syndr. 31, 478–482 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Cardiello, P.G. et al. Pharmacokinetics of once-daily saquinavir hard-gelatin capsules and saquinavir soft-gelatin capsules boosted with ritonavir in HIV-1-infected subjects. J. Acquir. Immune Defic. Syndr. 32, 375–379 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Cvetkovic, R.S. & Goa, K.L. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs 63, 769–802 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. AIDS—United States, 2000. MMWR Morb. Mortal. Wkly. Rep. 51, 592–595 (2002).

  38. Sendi, P., Palmer, A.J., Gafni, A. & Battegay, M. Highly active antiretroviral therapy: pharmacoeconomic issues in the management of HIV infection. Pharmacoeconomics 19, 709–713 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Gallant, J.E. Strategies for long-term success in the treatment of HIV infection. JAMA 283, 1329–1334 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Hirsch, M.S. et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. JAMA 283, 2417–2426 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Shafer, R.W. Genotypic testing for human immunodeficiency virus type 1 drug resistance. Clin. Microbiol. Rev. 15, 247–277 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Durant, J. et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet 353, 2195–2199 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Baxter, J. et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS 14, F83–93 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Pomerantz, R.J. Primary HIV-1 resistance: a new phase in the epidemic? JAMA 282, 1177–1179 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Little, S.J. et al. Antiretroviral-drug resistance among patients recently infected with HIV. N. Engl. J. Med. 347, 385–394 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Haggerty, S. & Stevenson, M. Predominance of distinct viral genotypes in brain and lymph node compartments of HIV-1-infected individuals. Viral Immunol. 4, 123–131 (1991).

    Article  CAS  PubMed  Google Scholar 

  47. Zhu, T. et al. Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: evidence for viral compartmentalization and selection during sexual transmission. J. Virol. 70, 3098–3107 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Overbaugh, J., Anderson, R.J., Ndinya-Achola, J.O. & Kreiss, J.K. Distinct but related human immunodeficiency virus type 1 variant populations in genital secretions and blood. AIDS Res. Hum. Retroviruses 12, 107–115 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Zhang, H. et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N. Engl. J. Med. 339, 1803–1809 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Wong, J.K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291–1295 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Pomerantz, R.J. Residual HIV-1 infection during antiretroviral therapy: the challenge of viral persistence. AIDS 15, 1201–1211 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Dornadula, G. et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA 282, 1627–1632 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Dornadula, G. et al. Human immunodeficiency virus type 1-infected persons with residual disease and virus reservoirs on suppressive highly active antiretroviral therapy can be stratified into relevant virologic and immunologic subgroups. J. Infect. Dis. 183, 1682–1687 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Kulkosky, J. et al. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J. Infect. Dis. 186, 1403–1411 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Kulkosky, J. et al. Genotypic alteration of HAART-persistant HIV-1 reservoirs in vivo. Virology (in the press).

  57. Kulkosky, J. & Pomerantz, R.J. Approaching eradication of highly active antiretroviral therapy-persistent human immunodeficiency virus type 1 reservoirs with immune activation therapy. Clin. Infect. Dis. 35, 1520–1526 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Pomerantz, R.J. Reservoirs of human immunodeficiency virus type 1: the main obstacles to viral eradication. Clin. Infect. Dis. 34, 91–97 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Li, T.S. et al. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 351, 1682–1686 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Autran, B. et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277, 112–116 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Dybul, M. et al. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR Recomm. Rep. 51, 1–55 (2002).

    PubMed  Google Scholar 

  62. Ho, D.D. Time to hit HIV, early and hard. N. Engl. J. Med. 333, 450–451 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Palella, F.J. et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Ann. Intern. Med. 138, 620–626 (2003).

    Article  PubMed  Google Scholar 

  64. Minkoff, H. Human immunodeficiency virus infection in pregnancy. Obstet. Gynecol. 101, 797–810 (2003).

    PubMed  Google Scholar 

  65. Lalezari, J.P. et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med. (2003).

  66. Kilby, J.M. et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat. Med. 4, 1302–1307 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Kilby, J.M. et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res. Hum. Retroviruses 18, 685–693 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Gulick, R.M. New antiretroviral drugs. Clin. Microbiol. Infect. 9, 186–193 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Farmer, P. The major infectious diseases in the world—to treat or not to treat? N. Engl. J. Med. 345, 208–210 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Bozzette, S.A. et al. The care of HIV-infected adults in the United States. HIV Cost and Services Utilization Study Consortium. N. Engl. J. Med. 339, 1897–1904 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Hellinger, F.J. & Fleishman, J.A. Estimating the national cost of treating people with HIV disease: patient, payer, and provider data. J. Acquir. Immune Defic. Syndr. 24, 182–188 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Dybul, M. Structured treatment interruption: approaches and risks. Curr. Infect. Dis. Rep. 4, 175–180 (2002).

    Article  PubMed  Google Scholar 

  73. Garcia, F. et al. The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. AIDS 15, F29–F40 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Hardy, G.A., Imami, N. & Gotch, F.M. Improving HIV-specific immune responses in HIV-infected patients. J. HIV Ther. 7, 40–45 (2002).

    CAS  PubMed  Google Scholar 

  75. Caulfield, M.J. et al. Sustained peptide-specific γ interferon T-cell response in rhesus macaques immunized with human immunodeficiency virus gag DNA vaccines. J. Virol. 76, 10038–10043 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pantaleo, G. et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N. Engl. J. Med. 332, 209–216 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. Rosenberg, E.S. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Frankel, A.D. & Young, J.A. HIV-1: fifteen proteins and an RNA. Annu. Rev. Biochem. 67, 1–25 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Grobler, J.A. et al. Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. USA 99, 6661–6666 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Baba, M. et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 96, 5698–5703 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Donzella, G.A. et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat. Med. 4, 72–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. De Clercq, E. New anti-HIV agents and targets. Med. Res. Rev. 22, 531–565 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Yang, B. et al. Potent suppression of viral infectivity by the peptides that inhibit multimerization of human immunodeficiency virus type 1 (HIV-1) Vif proteins. J. Biol. Chem. 278, 6596–6602 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Gaddis, N.C., Chertova, E., Sheehy, A.M., Henderson, L.E. & Malim, M.H. Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions. J. Virol. 77, 5810–5820 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sheehy, A.M., Gaddis, N.C., Choi, J.D. & Malim, M.H. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646–650 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Alexander, L., Aquino-DeJesus, M.J., Chan, M. & Andiman, W.A. Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by a two-amino-acid insertion in HIV-1 Vif from a nonprogressing mother and child. J. Virol. 76, 10533–10539 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Turner, B.G. & Summers, M.F. Structural biology of HIV. J. Mol. Biol. 285, 1–32 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R.M. Victor and B.O. Gordon for excellent secretarial assistance. This work was supported in part by National Institutes of Health grant AI46289 to R.J.P.

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  1. Division of Infectious Diseases and Environmental Medicine, Department of Medicine, Center for Human Virology and Biodefense, Jefferson Medical College, Thomas Jefferson University, 1020 Locust Street, Suite 329, Philadelphia, 19107, Pennsylvania, USA

    Roger J Pomerantz & David L Horn

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Pomerantz, R., Horn, D. Twenty years of therapy for HIV-1 infection. Nat Med 9, 867–873 (2003). https://doi.org/10.1038/nm0703-867

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