Role of Gag in HIV Resistance to Protease Inhibitors

Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. Howeve...

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Autores principales: Clavel, François, Mammano, Fabrizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185719/
https://www.ncbi.nlm.nih.gov/pubmed/21994687
http://dx.doi.org/10.3390/v2071411
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author Clavel, François
Mammano, Fabrizio
author_facet Clavel, François
Mammano, Fabrizio
author_sort Clavel, François
collection PubMed
description Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. However, as with all other antiretroviral drugs, the clinical benefit of protease inhibitors can be compromised by resistance. One key feature of HIV resistance to protease inhibitors is that the mutations that promote resistance are not only located in the protease itself, but also in some of its natural substrates. The best documented resistance-associated substrate mutations are located in, or near, the cleavage sites in the NC/SP2/p6 region of Gag. These mutations improve interactions between the substrate and the mutated enzyme and correspondingly increase cleavage. Initially described as compensatory mutations able to partially correct the loss of viral fitness that results from protease mutations, changes in Gag are now recognized as being directly involved in resistance. Besides NC/SP2/p6 mutations, polymorphisms in other regions of Gag have been found to exert various effects on viral fitness and or resistance, but their importance deserves further evaluation.
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spelling pubmed-31857192011-10-12 Role of Gag in HIV Resistance to Protease Inhibitors Clavel, François Mammano, Fabrizio Viruses Review Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. However, as with all other antiretroviral drugs, the clinical benefit of protease inhibitors can be compromised by resistance. One key feature of HIV resistance to protease inhibitors is that the mutations that promote resistance are not only located in the protease itself, but also in some of its natural substrates. The best documented resistance-associated substrate mutations are located in, or near, the cleavage sites in the NC/SP2/p6 region of Gag. These mutations improve interactions between the substrate and the mutated enzyme and correspondingly increase cleavage. Initially described as compensatory mutations able to partially correct the loss of viral fitness that results from protease mutations, changes in Gag are now recognized as being directly involved in resistance. Besides NC/SP2/p6 mutations, polymorphisms in other regions of Gag have been found to exert various effects on viral fitness and or resistance, but their importance deserves further evaluation. Molecular Diversity Preservation International (MDPI) 2010-07-05 /pmc/articles/PMC3185719/ /pubmed/21994687 http://dx.doi.org/10.3390/v2071411 Text en © 2010 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Review
Clavel, François
Mammano, Fabrizio
Role of Gag in HIV Resistance to Protease Inhibitors
title Role of Gag in HIV Resistance to Protease Inhibitors
title_full Role of Gag in HIV Resistance to Protease Inhibitors
title_fullStr Role of Gag in HIV Resistance to Protease Inhibitors
title_full_unstemmed Role of Gag in HIV Resistance to Protease Inhibitors
title_short Role of Gag in HIV Resistance to Protease Inhibitors
title_sort role of gag in hiv resistance to protease inhibitors
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185719/
https://www.ncbi.nlm.nih.gov/pubmed/21994687
http://dx.doi.org/10.3390/v2071411
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