Conservation patterns of HIV-1 RT connection and RNase H domains: identification of new mutations in NRTI- treated patients

• Autor(es): Santos, André Felipe Andrade dos ; Lengruber, Renan Bohrer ; Soares, Esmeralda Augusta Jardim Machado ; Jere, Abhay ; Sprinz, Eduardo ; Martinez, Ana Maria Barral de ; Silveira, Jussara Maria ; Sion, Fernando Samuel ; Pathak, Vinay Kumar ; Soares, Marcelo Alves
• Data: 2013
• Origem: Oasisbr
• Tipo de Documento: Artigo científico
• Idioma: Inglês

Descrição

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Background: Although extensive HIV drug resistance information is available for the first 400 amino acids of its reverse transcriptase, the impact of antiretroviral treatment in C-terminal domains of Pol (thumb, connection and RNase H) is poorly understood. Methods and Findings: We wanted to characterize conserved regions in RT C-terminal domains among HIV-1 group M subtypes and CRF. Additionally, we wished to identify NRTI-related mutations in HIV-1 RT C-terminal domains. We sequenced 118 RNase H domains from clinical viral isolates in Brazil, and analyzed 510 thumb and connection domain and 450 RNase H domain sequences collected from public HIV sequence databases, together with their treatment status and histories. Drug-naıve and NRTI-treated datasets were compared for intra- and inter-group conservation, and differences were determined using Fisher’s exact tests. One third of RT C-terminal residues were found to be conserved among group M variants. Three mutations were found exclusively in NRTI-treated isolates. Nine mutations in the connection and 6 mutations in the RNase H were associated with NRTI treatment in subtype B. Some of them lay in or close to amino acid residues which contact nucleic acid or near the RNase H active site. Several of the residues pointed out herein have been recently associated to NRTI exposure or increase drug resistance to NRTI. Conclusions: This is the first comprehensive genotypic analysis of a large sequence dataset that describes NRTI-related mutations in HIV-1 RT C-terminal domains in vivo. The findings into the conservation of RT C-terminal domains may pave the way to more rational drug design initiatives targeting those regions.