Three Main Mutational Pathways in HIV-2 Lead to High-Level Raltegravir and Elvitegravir Resistance: Implications for Emerging HIV-2 Treatment RegimensReportar como inadecuado




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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.



Autor: Robert A. Smith , Dana N. Raugi, Charlotte Pan, Matthew Coyne, Alexandra Hernandez, Brad Church, Kara Parker, James I. Mullins, P

Fuente: http://plos.srce.hr/



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