Review Article | Published:

HIV chemotherapy

Nature volume 410, pages 9951001 (19 April 2001) | Download Citation

Subjects

Abstract

The use of chemotherapy to suppress replication of the human immunodeficiency virus (HIV) has transformed the face of AIDS in the developed world. Pronounced reductions in illness and death have been achieved and healthcare utilization has diminished. HIV therapy has also provided many new insights into the pathogenesis and the viral and cellular dynamics of HIV infection. But challenges remain. Treatment does not suppress HIV replication in all patients, and the emergence of drug-resistant virus hinders subsequent treatment. Chronic therapy can also result in toxicity. These challenges prompt the search for new drugs and new therapeutic strategies to control chronic viral replication.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Viral dynamics of HIV: implications for drug development and therapeutic strategies. Ann. Intern. Med. 124, 984–994 (1996).

  2. 2.

    et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259, 1749–1754 (1993).

  3. 3.

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

  4. 4.

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

  5. 5.

    , , & Polygenic and multifactorial disease gene association in man: lessons from AIDS. Ann. Rev. Genet. 34, 563–591 (2000).

  6. 6.

    & The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol. Rev. 177, 99–111 (2000).

  7. 7.

    , , , & HIV-1 dynamics in vivo: virion clearance rate, infected cell lifetime, and viral generation time. Science 271, 1582–1586 (1996).

  8. 8.

    et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985–989 (1996).

  9. 9.

    Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Ann. Rev. Immunol. 17, 625–656 (1999).

  10. 10.

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

  11. 11.

    C. J. et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA panel. J. Am. Med. Assoc. 283, 381–390 (2000).

  12. 12.

    et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431 (1998).

  13. 13.

    , , , & Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science 284, 816–819 (1999).

  14. 14.

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

  15. 15.

    et al. HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies. Virology 180, 583–590 (1991).

  16. 16.

    et al. In vivo compartmentalization of HIV: evidence from the examination of pol sequences from autopsy tissues. J. Virol. 70, 2059–2071 (1997).

  17. 17.

    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).

  18. 18.

    , , & Distinct but related human immunodeficiency virus type 1 variant populations in genital secretions and blood. AIDS Res. Hum. Retroviruses 12, 107–115 (1996).

  19. 19.

    et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291–1294 (1997).

  20. 20.

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

  21. 21.

    et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193–13197 (1997).

  22. 22.

    et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Med. 5, 512–517 (1999).

  23. 23.

    et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nature Med. 6, 82–85 (2000).

  24. 24.

    et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188–191 (1997).

  25. 25.

    et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276, 960–964 (1997).

  26. 26.

    et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286, 1353–1357 (1999).

  27. 27.

    et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. J. Am. Med. Assoc. 282, 1627–1632 (1999).

  28. 28.

    et al. Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy. J. Virol. 73, 9404–9412 (1999).

  29. 29.

    et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N. Engl. J. Med. 340, 1614–1622 (1999).

  30. 30.

    et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nature Med. 6, 76–81 (2000).

  31. 31.

    et al. Time of initiation of antiretroviral therapy: impact on HIV-1 viraemia. AIDS 14, 243–249 (2000).

  32. 32.

    et al. Residual HIV-RNA levels persist for up to 2.5 years in peripheral blood mononuclear cells of patients on potent antiretroviral therapy. AIDS Res. Hum. Retroviruses 16, 1135–1140 (2000).

  33. 33.

    et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N. Engl. J. Med. 337, 734–739 (1997).

  34. 34.

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

  35. 35.

    et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nature Med. 4, 208–214 (1998).

  36. 36.

    et al. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS clinical trials group protocol 315. J. Infect. Dis. 178, 70–79 (1998).

  37. 37.

    et al. Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc. Natl Acad. Sci. USA 95, 1154–1159 (1998).

  38. 38.

    et al. Initial increase in blood CD4+ lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues. J. Clin. Invest. 103, 1391–1398 (1999).

  39. 39.

    et al. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J. Clin. Invest. 101, 2301–2308 (1998).

  40. 40.

    et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1999).

  41. 41.

    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).

  42. 42.

    et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nature Med. 4, 953–956 (1998).

  43. 43.

    et al. Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects. J. Infect. Dis. 182, 1658–1663 (2000).

  44. 44.

    Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. J. Am. Med. Assoc. 283, 653–657 (2000).

  45. 45.

    et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J. Infect. Dis. 179, 697–700 (1999).

  46. 46.

    et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet 351, 252–255 (1998).

  47. 47.

    & Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N. Engl. J. Med. 342, 1416–1429 (2000).

  48. 48.

    et al. Impact of protease inhibitors on AIDS-defining events and hospitalization in 10 French AIDS reference centres. AIDS 11, F101–F105 (1997).

  49. 49.

    Centers for Disease Control and Prevention. HIV/AIDS Surveillance Rep. 10, 1–43 (1998).

  50. 50.

    et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 352, 1725–1730 (1998).

  51. 51.

    et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N. Engl. J. Med. 338, 853–860 (1998).

  52. 52.

    , , , & Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256, 1783–1790 (1992).

  53. 53.

    et al. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 92, 1222–1226 (1995).

  54. 54.

    et al. The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group. AIDS 13, 1099–1107 (1999).

  55. 55.

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

  56. 56.

    et al. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study. AIDS 14, 1333–1339 (2000).

  57. 57.

    et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS 13, 2083–2089 (1999).

  58. 58.

    HIV-protease inhibitors. N. Engl. J. Med. 338, 1281–1292 (1998).

  59. 59.

    et al. Antiretroviral drugs and the central nervous system. AIDS 12, 1941–1955 (1998).

  60. 60.

    et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101, 289–294 (1998).

  61. 61.

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

  62. 62.

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

  63. 63.

    , , & 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).

  64. 64.

    & Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J. Virol. 69, 5087–5094 (1995).

  65. 65.

    Transmission and prevalence of HIV resistance among treatment-naive subjects. Antivir. Ther. 5, 33–40 (2000).

  66. 66.

    et al. Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. Investigators of the Quebec Primary Infection Study. AIDS 14, F17–F23 (2000).

  67. 67.

    et al. Antiretroviral drug resistance testing in adults with HIV infection. J. Am. Med. Assoc. 279, 1984–1991 (1998).

  68. 68.

    et al. Antiretroviral drug resistance testing in adult HIV-1 infection. J. Am. Med. Assoc. 283, 2417–2426 (2000).

  69. 69.

    et al. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 44, 920–928 (2000).

  70. 70.

    et al. The accuracy and reproducibility of high throughput genotypic and phenotypic HIV-1 resistance testing under EN45001 and CLIA accreditation labels. Antivir. Ther. 4(Suppl. 1), 53 (1999).

  71. 71.

    et al. The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan. Antivir. Ther. 5, 41–48 (2000).

  72. 72.

    et al. Persisting long-term benefit of genotype-guided treatment for HIV- infected patients failing HAART. The Viradapt Study: week 48 follow-up. Antivir Ther 5, 65–70 (2000).

  73. 73.

    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–F93 (2000).

  74. 74.

    et al. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J. Infect. Dis. 182, 758–765 (2000).

  75. 75.

    et al. Identification of clinically relevant phenotypic and genotypic breakpoints for ABT-378/r in multiple PI-experience, NNRTI-naive patients. Antivir. Ther. 5(Suppl. 3), 70 (2000).

  76. 76.

    et al. R165335-TMC125, a novel non nucleoside reverse transcriptase inhibitor (NNRTI) with nanomolar activity against NNRTI resistant HIV strains. AIDS 14(Suppl. 4), PL4.5 (2000).

  77. 77.

    et al. Inhibitors of HIV nucleocapsid protein zinc fingers as candidates for the treatment of AIDS. Science 270, 1194–1197 (1995).

  78. 78.

    et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646–650 (2000).

  79. 79.

    & New targets for inhibitors of HIV-1 replication. Nature Rev. Mol. Cell Biol. 1, 40–49 (2000).

  80. 80.

    , , & Core structure of gp41 from the HIV envelope glycoprotein. Cell 89, 263–273 (1997).

  81. 81.

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

  82. 82.

    , & Protein design of an HIV-1 entry inhibitor. Science 291, 884–888 (2001).

  83. 83.

    et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nature Med. 4, 72–77 (1999).

  84. 84.

    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).

  85. 85.

    et al. The care of HIV-infected adults in the United States. N. Engl. J. Med. 339, 1897–1904 (1998).

  86. 86.

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

  87. 87.

    , , , & Costs of HIV medical care in the era of highly active antiretroviral therapy. AIDS 13, 963–969 (1999).

  88. 88.

    et al. Protease inhibitor-based therapy is associated with decreased HIV-related health care costs in men treated at a Veterans Administration hospital. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 20, 28–33 (1999).

  89. 89.

    Cost effectiveness of combination HIV therapy: 3 years later. Pharmacoeconomics 17, 325–330 (2000).

  90. 90.

    S. The affordability of antiretroviral therapy in developing countries: what policymakers need to know. AIDS 12(Suppl 2), S11–S18 (1998).

  91. 91.

    et al. Variations in the care of HIV-infected adults in the United States. J. Am. Med. Assoc. 281, 2305–2315 (2000).

  92. 92.

    et al. Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet 354, 803–809 (1999).

  93. 93.

    et al. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. J. Am. Med. Assoc. 283, 1175–1182 (2000).

  94. 94.

    , , & Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J. Exp. Med. 177, 249–256 (1993).

  95. 95.

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

  96. 96.

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

  97. 97.

    et al. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J. Exp. Med. 181, 1365–1372 (1995).

  98. 98.

    et al. Quantitation of HIV-1 specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279, 2103–2106 (1998).

  99. 99.

    et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).

  100. 100.

    et al. Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J. Virol. 72, 164–169 (1998).

  101. 101.

    et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).

  102. 102.

    et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189, 991–998 (1999).

  103. 103.

    et al. Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523–526 (2000).

  104. 104.

    et al. Control of SIV rebound through structured treatment interruptions during early infection. Science 290, 1591–1593 (2000).

  105. 105.

    et al. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290, 486–492 (2000).

  106. 106.

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

  107. 107.

    Centers for Disease Control and Prevention. AIDS Surveillance—Trends 〈〉 Divisions of HIV/AIDS Prevention, National Center for HIV, STD and TB Prevention (11 December 2000).

  108. 108.

    F. Hoffmann-La Roche, Ltd. The multimedia lifecycle of HIV 〈http://www.roche-hiv.com (1999).

Download references

Acknowledgements

A limited review of such an extensive field can achieve neither completeness nor balance. I apologize to my many colleagues whose contributions have not been explicitly acknowledged. D.R. is supported by grants from the UCSD Center for AIDS Research, the National Institutes of Health, and the Research Center for AIDS and HIV Infection of the Veterans Affairs San Diego Healthcare System.

Author information

Corresponding author

Correspondence to Douglas D. Richman.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/35073673

Authors

  1. Search for Douglas D. Richman in:

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing