Ordered accumulation of mutations in HIV protease confers resistance to ritonavir

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.

Analysis of HIV-1 CRF_01 A/E Protease Inhibitor Resistance: Structural Determinants for Maintaining Sensitivity and Developing Resistance to Atazanavir

“…Though the natural polymorphisms found in AE when compared to the B protease have arisen in the absence of PI therapy, residue changes in AE at positions 35, 36, 37, 41, 69, and 89 have been associated with PI resistance in vivo and in vitro in B proteases (17)(18)(19)(20). Thus, these polymorphisms can potentially influence substrate processing and the binding of currently available PIs and/or facilitate the development of resistance.…”

Human immunodeficiency virus type 1: drug resistance in treated and untreated Brazilian children

“…It was detected in 5 of the 9 samples showing PIs resistance mutations. The V82A occurs predominantly in HIV-1 isolates from patients receiving treatment with IDV or RTV (Condra et al 1996, Molla et al 1996. By themselves, mutations at position 82 confer reduced susceptibility in vitro to IDV, RTV, and LPV but not to NFV, SQV, or APV (Kempf et al 2001).…”

HIV-1 evolution under pressure of protease inhibitors: Climbing the stairs of viral fitness

“…The exact evolutionary pathway will depend not only on the type ofprotease inhibitor, but also on the viral genetic background [48] and stochastic events [32]. There is a certain order in the accumulation of mutations, but this pattern may vary significantly within individual patients [40]. Most of the initial resistance mutations in the protease enzyme are located proximal to the drug-binding site, resulting in direct steric perturbation of the drug-enzyme interaction [46].…”