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

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

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 1

PI pharmacodynamics.

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PI pharmacodynamics. (A) Representations of the dose-response curves for...
(A) Representations of the dose-response curves for the PI ATV. Primary CD4+ T cells were infected with viruses generated in the presence of various ATV concentrations, and fu was measured as previously described (2). Left panel: conventional semi-log dose-response curve in which fu is plotted against log D (normalized by IC50). Conventional plots obscure the differences between the ATV curve and the curve for a hypothetical drug with the same IC50 and an m value of 1 (dotted line). Middle panel: log-log of the dose-response curve. Right panel: median effect plot, log [(1 – fu)/fu] vs. log D/IC50. This plot, based on Equation 2, linearizes most dose-response curves, resulting in lines whose slopes are equal to the slope parameter m in Equations 1 and 2. This plot illustrates the steep slope and upward inflection of PI dose-response curves. (B) PIs may inhibit multiple steps in the life cycle. PIs block maturation of the virus particle (green arrow). Since maturation begins concomitantly with budding, an effect on budding is possible. Viruses that fail to mature due to the action of PIs could be blocked at downstream steps including entry, reverse transcription, and integration. (C) If PIs block multiple steps, then Bliss independence predicts that the fraction of successful infection events is the product of the fraction of viruses that pass each block. The maximal slope of the overall dose-response curve is the sum of the slopes of the dose-response curves for each step (Supplemental Appendix 1).