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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
agricultural and biological sciences
Gag determinants of fitness and drug susceptibility in protease inhibitor-resistant human immunodeficiency virus type 1
Journal of Virology, Volume 83, No. 18, Year 2009
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Description
Mutations can accumulate in the protease and gag genes of human immunodeficiency virus in patients who fail therapy with protease inhibitor drugs. Mutations within protease, the drug target, have been extensively studied. Mutations in gag have been less well studied, mostly concentrating on cleavage sites. A retroviral vector system has been adapted to study full-length gag, protease, and reverse transcriptase genes from patient-derived viruses. Patient plasma-derived mutant full-length gag, protease, and gag-protease from a multidrug-resistant virus were studied. Mutant protease alone led to a 95% drop in replication capacity that was completely rescued by coexpressing the full-length coevolved mutant gag gene. Cleavage site mutations have been shown to improve the replication capacity of mutated protease. Strikingly, in this study, the matrix region and part of the capsid region from the coevolved mutant gag gene were sufficient to achieve full recovery of replication capacity due to the mutant protease, without cleavage site mutations. The same region of gag from a second, unrelated, multidrug-resistant clinical isolate also rescued the replication capacity of the original mutant protease, suggesting a common mechanism that evolves with resistance to protease inhibitors. Mutant gag alone conferred reduced susceptibility to all protease inhibitors and acted synergistically when linked to mutant protease. The matrix region and partial capsid region of gag sufficient to rescue replication capacity also conferred resistance to protease inhibitors. Thus, the amino terminus of Gag has a previously unidentified and important function in protease inhibitor susceptibility and replication capacity. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Parry, Chris M.
United Kingdom, London
University College London
United Kingdom, London
Public Health England
Boinett, Christine J.
United Kingdom, London
University College London
Towers, Greg J.
United Kingdom, London
University College London
McCormick, Adele L.
United Kingdom, London
University College London
Morris, Lynn G.
United Kingdom, London
University College London
United Kingdom, London
Public Health England
Statistics
Citations: 70
Authors: 5
Affiliations: 3
Identifiers
Doi:
10.1128/JVI.02356-08
ISSN:
0022538X
Research Areas
Genetics And Genomics
Health System And Policy