In Vitro Isolation and Identification of Human Immunodeficiency Virus (HIV) Variants with Reduced Sensitivity to C-2 Symmetrical Inhibitors of HIV Type 1 Protease

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1993 Aug 15

PMID 8356053

Citations 41

Authors

M J Otto

S Garber

D L Winslow

C D Reid

P ALDRICH

P K Jadhav

C E PATTERSON

C N Hodge

Y S Cheng

Affiliations

Soon will be listed here.

Abstract

Protease inhibitors are another class of compounds for treatment of human immunodeficiency virus (HIV)-caused disease. The emergence of resistance to the current anti-HIV drugs makes the determination of potential resistance to protease inhibitors imperative. Here we describe the isolation of an HIV type 1 (HIV-1) resistant to an HIV-protease inhibitor. Serial passage of HIV-1 (strain RF) in the presence of the inhibitor, [2-pyridylacetylisoleucylphenylalanyl-psi (CHOH)]2 (P9941), failed to yield a stock of virus with a resistance phenotype. However, variants of the virus with 6- to 8-fold reduced sensitivity to P9941 were selected by using a combination of plaque assay and endpoint titration. Genetic analysis and computer modeling of the variant proteases revealed a single change in the codon for amino acid 82 (Val-->Ala), which resulted in a protease with lower affinity and reduced sensitivity to this inhibitor and certain, but not all, related inhibitors.

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