Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 p6 protein.

Détails

ID Serval
serval:BIB_645EBB92B1B7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 p6 protein.
Périodique
Journal of virology
Auteur(s)
Peters S., Muñoz M., Yerly S., Sanchez-Merino V., Lopez-Galindez C., Perrin L., Larder B., Cmarko D., Fakan S., Meylan P., Telenti A.
ISSN
0022-538X
Statut éditorial
Publié
Date de publication
2001
Peer-reviewed
Oui
Volume
75
Numéro
20
Pages
9644-53
Langue
anglais
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't - Publication Status: ppublish
Résumé
Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the pol gene, which encodes the viral protease, reverse transcriptase (RT), and integrase. We speculated that mutations in genes other that the drug target could lead to drug resistance. For this purpose, the p1-p6(gag)-p6(pol) region of HIV-1, placed immediately upstream of pol, was analyzed. This region has the potential to alter Pol through frameshift regulation (p1), through improved packaging of viral enzymes (p6(Gag)), or by changes in activation of the viral protease (p6(Pol)). Duplication of the proline-rich p6(Gag) PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog RT inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drug-naïve individuals. Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in p6(Pol)), displayed a delay in protein maturation; however, they packaged a 34% excess of RT and exhibited a marked competitive growth advantage in the presence of NRTIs. This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro. Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.
Mots-clé
Amino Acid Sequence, Anti-HIV Agents, Base Sequence, Cloning, Molecular, Drug Resistance, Microbial, Gene Products, gag, Genes, Viral, HIV Infections, HIV-1, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Polymorphism, Genetic, Proline, Reverse Transcriptase Inhibitors, Viral Proteins, gag Gene Products, Human Immunodeficiency Virus
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2008 15:45
Dernière modification de la notice
20/08/2019 15:20
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