7th Conference

LB9 Novel Amino Acid Change Influencing Susceptibility to Nevirapine Detected in Primary HIV Infection.

A. J. LEIGH BROWN*, H. M. PRECIOUS, J. WHITCOMB, E. DAAR, R. T. D'AQUILA, P. KEISER, E. CONNICK, N. HELLMANN, C. PETROPOULOS, J. K. WONG, D. D. RICHMAN, and S. J. LITTLE. Univ. of Edinburgh, Scotland; Univ. of California San Diego; ViroLogic, South San Francisco, CA; Cedars Sinai Med. Ctr., Los Angeles, CA; Massachusetts Gen. Hosp., Boston; Univ. of Texas, Dallas; and Univ. of Colorado Hlth. Sci. Ctr., Denver.

Antiretroviral susceptibility testing was performed on 109 treatment-naïve individuals with primary HIV infection using the PhenoSense HIV assay. Thirteen patient samples showed reduced susceptibility (2.5 - 7 fold reduction) to nevirapine. Amino acid (aa) sequences of the HIV reverse transcriptase (RT) coding domain (aa 1-305) from these subjects were analyzed for variation correlating with the differences in susceptibility using logistic regression. 46 aa sites in RT (15%) showed a variant in samples from 5 or more individuals. Two sites were identified in the logistic regression: L283I (odds ratio 28, P < 0.0003) and I135T/V (odds ratio 5.8, P < 0.007). I135T/V, but not L283I was also associated with reduced susceptibility to delavirdine in this study. The median fold reduction in susceptibility to nevirapine for viruses bearing L283I (n = 7) relative to those bearing 283L was 2.8; 5 of the 7 mutants at this site were among those classified as having reduced susceptibility. The median fold reduction for aa 135 mutants (n = 36) was 1.7. Multiple regression with stepwise selection was applied to all variable sites taken together and identified 283, 200, 98 & 135 as the 4 sites with the largest joint effect.

The significance of these results is two-fold: first the distribution of reduced susceptibility to nevirapine in subjects with primary HIV infection is associated with variation at a very limited number of amino acid sites. Secondly, L283I, a previously reported polymorphism located in the “thumb” region of p66 and unexpectedly associated with differences in susceptibility, probably imparts conformational rather than direct effects on the active site of RT.

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