CONICET | Buscador de Institutos y Recursos Humanos

Sub-optimal treatment of HIV-1 infection with non-nucleoside reverse transcriptase inhibitors (NNRTI) often results in the rapid selection of drug resistant virus. Several amino acid substitutions at position 190 of reverse transcriptase have been associated with reduced susceptibility to the NNRTI, especially nevirapine and efavirenz. In this study, the effects of various 190 substitutions observed in viruses obtained from NNRTI-experienced patients were characterized using patient-derived HIV isolates and confirmed using a panel of isogenic viruses. Compared to wild-type HIV, which has a glycine at position 190 (G190), viruses with 190 substitutions (A, C, Q, S, V, E, or T, collectively referred to as G190X substitutions) were markedly less susceptible to nevirapine and efavirenz. In contrast, delavirdine susceptibility of these G190X viruses increased from 3 to 300 fold (hypersusceptible) or was only slightly decreased. Replication capacity of viruses with certain 190 substitutions (C, Q, V, T and E) was severely impaired and was correlated with reduced virion-associated reverse transcriptase (RT) activity and incomplete protease (PR) processing of the viral p55gag polyprotein. These defects were the result of inadequate p160gagpol incorporation into virions. Compensatory mutations within RT and PR improved replication capacity, p55gag processing and reverse transcriptase activity, presumably through increased incorporation of p160gagpol into virions. We observe an inverse relationship between the degree of nevirapine/efavirenz resistance and the impairment of viral replication in viruses with substitutions at 190 in RT. These observations may have important implications for the future design and development of antiretroviral drugs that restrict the outgrowth of resistant variants with high replication capacity.

enviar mensaje