Identifying Mutations with Small Effects on Drug Resistance

A.J. Leigh Brown*, H.M. Precious, J. Whitcomb, J.K. Wong, M. Quigg, W. Huang, E. Daar, R.T. D'Aquila, P.Keiser, E.Connick, N. Hellmann, C. Petropoulos, D.D. Richman and S.J. Little

Recently, significant numbers of individuals with primary HIV infection have been found to be harboring viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naïve individuals was shown to have a susceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTIs) of between 2.5 and 10-fold lower than a wild-type control. No mutations that had previously been associated with antiretroviral resistance were observed in the reverse transcriptase (RT) domain of these strains. We have analyzed all variable amino acid sites in this dataset and have identified 2 novel sites influencing susceptibility to NNRTIs: amino acid 135 and amino acid 283 in RT. The 8 different combinations of amino acids at these sites were found to have a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with an HIV drug resistance phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to these drugs.

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