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The Genotypic Basis of Moderately Reduced Susceptibility to Antiretroviral Drugs in Primary HIV Infection H. M. PRECIOUS1, S. J. LITTLE2, J. K. WONG2, J. WHITCOMB3, N. HELLMANN3, C. J. PETROPOULOS3, D. D. RICHMAN2, and A. J. LEIGH BROWN*1. 1Univ. of Edinburgh, Scotland; 2Univ. of California at San Diego; and 3ViroLogic, South San Francisco, CA Amino acid (aa) sequences of the RT and PR domains were analyzed from 43 antiretroviral-naïve subjects with primary HIV infection for whom baseline plasma samples were either fully susceptible or showed moderately reduced susceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PI). The median reduction in the PhenoSense HIV susceptibility assay in the latter individuals compared to the NL4-3 reference virus, was 4.0-fold for delavirdine, 3.4-fold for nelfinavir and 4.8-fold for ritonavir. The contribution of each aa site at which a variant was observed in RT or PR in 5 or more individuals was analyzed using logistic regression. Multiple regression with stepwise selection was then applied to all variable sites taken together. The initial analysis of PR sequences identified 3 significant sites each for nelfinavir and ritonavir. Sites 93, 63 and 77 for nelfinavir and 71, 62 and 36 for ritonavir individually explained a significant proportion of the variation in susceptibility among these individuals. Stepwise multiple regression identified the combinations 93 & 63 and 71 & 62, respectively, as explaining significantly more of the variation in susceptibility to these PIs than any aa site on its own. While no site was identified as influencing susceptibility to nevirapine, two sites in RT were found to have significant effects on susceptibility to delavirdine. Site aa135 had a log-odds ratio of 8.0 (P < 0.01); aa 162 was also significant individually and the pair was selected by stepwise multiple regression. Thus, the moderate reduction in susceptibility seen in a subset of subjects with primary HIV infection is due to variation in HIV RT and PR at aa sites not previously associated with antiretroviral resistance. Key Words: Phenotypic assay, Primary Infection, Resistance |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |