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Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance
S. Alireza Rabi, … , Richard D. Moore, Robert F. Siliciano
S. Alireza Rabi, … , Richard D. Moore, Robert F. Siliciano
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):3848-3860. https://doi.org/10.1172/JCI67399.
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Research Article Article has an altmetric score of 31

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

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Abstract

HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral drugs. They are characterized by highly cooperative dose-response curves that are not explained by current pharmacodynamic theory. An unresolved problem affecting the clinical use of PIs is that patients who fail PI-containing regimens often have virus that lacks protease mutations, in apparent violation of fundamental evolutionary theory. Here, we show that these unresolved issues can be explained through analysis of the effects of PIs on distinct steps in the viral life cycle. We found that PIs do not affect virion release from infected cells but block entry, reverse transcription, and post–reverse transcription steps. The overall dose-response curves could be reconstructed by combining the curves for each step using the Bliss independence principle, showing that independent inhibition of multiple distinct steps in the life cycle generates the highly cooperative dose-response curves that make these drugs uniquely effective. Approximately half of the inhibitory potential of PIs is manifest at the entry step, likely reflecting interactions between the uncleaved Gag and the cytoplasmic tail (CT) of the Env protein. Sequence changes in the CT alone, which are ignored in current clinical tests for PI resistance, conferred PI resistance, providing an explanation for PI failure without resistance.

Authors

S. Alireza Rabi, Gregory M. Laird, Christine M. Durand, Sarah Laskey, Liang Shan, Justin R. Bailey, Stanley Chioma, Richard D. Moore, Robert F. Siliciano

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Figure 6

Importance of the entry effect on the analysis of resistance to PIs.

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Importance of the entry effect on the analysis of resistance to PIs.
(A)...
(A) Dependence of pseudoviruses with MLV-E on HIV-1 protease for entry. HIV-1 pseudoviruses with WT or mutant (D25N) protease and the indicated forms of MLV-E were used to infect CD4+ lymphoblasts, and entry was measured by FRET. (B) Effect of PI treatment of virus-producing cells on the entry of pseudoviruses with MLV-E. Pseudoviruses with the indicated forms of MLV-E and WT protease were generated in the presence of increasing concentrations of DRV and tested for entry into primary CD4+ T lymphoblasts using FRET. (C) DRV-mediated inhibition of infection of CD4+ T lymphoblasts by HIV-1 pseudoviruses with WT (p15) or truncated (p12) MLV-E. Infection was assessed by GFP expression in target cells. (D) The effect of target cell type on PI dose-response curves. HIV-1 pseudoviruses with WT MLV-E generated in the presence of increasing concentrations of DRV were used to infect 293T cells or primary CD4+ T lymphoblasts. Infection was assessed by GFP expression in target cells. (E) Comparison of DRV dose-response curves in experimental systems representing the clinical assay for resistance (MLV-E/293T) or in vivo infection (HIV-1 Env/CD4). HIV-1 pseudoviruses with MLV-E or HIV-1 Env were generated in the presence of increasing concentrations of DRV and used to infect 293T cells or primary CD4+ T lymphoblasts. Infection was assessed by GFP expression in target cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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