Abstract
Analysis of the HIV protease gene from the plasma of HIV–infected patients revealed substitutions at nine different codons selected in response to monotherapy with the protease inhibitor ritonavir. Mutants at valine–82, although insufficient to confer resistance, appeared first in most patients. Significant phenotypic resistance required multiple mutations in HIV protease, which emerged subsequently in an ordered, stepwise fashion. The appearance of resistance mutations was delayed in patients with higher plasma levels of ritonavir. Early mutants retained susceptibility to structurally diverse protease inhibitors, suggesting that dual protease inhibitor therapy might increase the duration of viral suppression.
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References
Richman, D.D. Zidovudine resistance of human immunodeficiency virus. Rev. Infect. Dis. 12, S507–S512 (1990).
Kempf, D. et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc. Natl. Acad. Sci. USA 92, 2484–2488 (1995).
Danner, S.A. et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N. Engl. J. Med. 333, 1528–1533 (1995).
Markowitz, M. et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N. Engl. J. Med. 333, 1534–1539 (1995).
Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).
Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122 (1995).
Cameron, B. et al. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. Third Conference on Retroviruses and Opportunistic Infections, Washington, DC, Jan. 28–Feb. 1, 1996, Abstract LB6a.
Condra, J.H. et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 374, 569–571 (1995).
Pachl, C. et al. Rapid and precise quantification of HIV-1 RNA in plasma using a branched DNA signal amplification assay. J. Acquir. Immune Defic. Syndr. Hum. Retroviral. 8, 446–454 (1995).
Myers, G., Wain-Hobson, S., Korber, B., Smith, R.F. & Pavlakis, G.N. Human Retroviruses and AIDS (Los Alamos National Laboratory, Los Alamos, New Mexico, 1993).
Markowitz, M. et al. Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor. J. Virol. 69, 701 (1995).
Jacobsen, H. et al. In-vivo resistance to HIV proteinase inhibitor saquinavir—an update. AIDS Res. Hum. Retrovir. 11, S169–S169 (1995).
Pauwels, R. et al. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 20, 309–321 (1988).
Partaledis, J.A. et al. In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethy-lamino sulfonamide inhibitors of HIV-1 aspartyl protease. J. Virol. 69, 5228–5235 (1995).
Patick, A.K. et al. Antiviral and resistance studies of AG 1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob. Agents Chemother. 40, 292–297 (1996).
Schapiro, J.M. et al. The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann. Intern. Med. (in the press).
Heath-Chiozzi, M. et al. Anti-HIV activity and lymphocyte surrogate marker response dynamics to ritonavir therapy in advanced HIV immunodeficiency. Third Conference on Retroviruses and Opportunistic Infections, Washington, DC, Jan. 28–Feb. 1, 1996, Abstract LB6b.
Gulick, R. et al. Potent and sustained antiretroviral activity of indinavir in combination with zidovudine and lamivudine. Third Conference on Retroviruses and Opportunistic Infections, Washington, DC, Jan. 28–Feb. 1, 1996, Abstract LB7.
Perelson, A.S., Neumann, A.U., Markowitz, M., Leonard, J.M. & Ho, D.D. HIV-1 dynamics in vivo: Virion clearance rate, infected cell lifespan, and viral generation time. Science 271, 1582–1586 (1996).
Coffin, J.M. HIV population dynamics in vivo: Implications for genetic variation, pathogenesis, and therapy. Science 267, 483–489 (1995).
Ho, D.D. et al. Characterization of HIV-1 variants with increased resistance to a C 2 symmetric protease inhibitor. J. Virol. 68, 2016–2020 (1994).
Gulnik, S.V. et al. Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. Biochemistry 34, 9282–9287 (1995).
Jacobsen, H. et al. Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology 206, 527–534 (1995).
Kitchen, V.S. et al. Safety and activity of saquinavir in HIV infection. Lancet 345, 952–955 (1995).
Japour, A.J., et al. Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. Antimicrob. Agents Chemother. 37, 1095–1101 (1993).
Maschera, B., Furfine, E. & Blair, E.D. Analysis of resistance to human immunodeficiency virus type 1 protease inhibitors by using matched bacterial expression and proviral infection vectors. J. Virol. 69 5431–5436 (1995).
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Molla, A., Korneyeva, M., Gao, Q. et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med 2, 760–766 (1996). https://doi.org/10.1038/nm0796-760
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DOI: https://doi.org/10.1038/nm0796-760
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