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Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
Title | Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Smith, RA, Raugi, DN, Pan, C, Coyne, M, Hernandez, A, Church, B, Parker, K, Mullins, JI, Sow, PSalif, Gottlieb, GS |
Corporate Authors | University of Washington-Dakar HIV-2 Study Group |
Journal | PLoS One |
Volume | 7 |
Issue | 9 |
Pagination | e45372 |
Date Published | 2012 |
ISSN | 1932-6203 |
Keywords | Cell Line, Drug Resistance, Viral, HIV Integrase Inhibitors, HIV-2, Humans, Mutation, Pyrrolidinones, Quinolones, Signal Transduction, Virus Replication |
Abstract | Human immunodeficiency virus type 2 (HIV-2) is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and exhibits reduced susceptibility to several of the protease inhibitors used for antiretroviral therapy of HIV-1. Thus, there is a pressing need to identify new classes of antiretroviral agents that are active against HIV-2. Although recent data suggest that the integrase strand transfer inhibitors raltegravir and elvitegravir may be beneficial, mutations that are known to confer resistance to these drugs in HIV-1 have been reported in HIV-2 sequences from patients receiving raltegravir-containing regimens. To examine the phenotypic effects of mutations that emerge during raltegravir treatment, we constructed a panel of HIV-2 integrase variants using site-directed mutagenesis and measured the susceptibilities of the mutant strains to raltegravir and elvitegravir in culture. The effects of single and multiple amino acid changes on HIV-2 replication capacity were also evaluated. Our results demonstrate that secondary replacements in the integrase protein play key roles in the development of integrase inhibitor resistance in HIV-2. Collectively, our data define three major mutational pathways to high-level raltegravir and elvitegravir resistance: i) E92Q+Y143C or T97A+Y143C, ii) G140S+Q148R, and iii) E92Q+N155H. These findings preclude the sequential use of raltegravir and elvitegravir (or vice versa) for HIV-2 treatment and provide important information for clinical monitoring of integrase inhibitor resistance in HIV-2-infected individuals. |
DOI | 10.1371/journal.pone.0045372 |
Alternate Journal | PLoS ONE |
PubMed ID | 23028968 |