Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) frompatients with primary HIV infection to nonnucleoside reverse transcriptaseinhibitors is associated with variation at novel amino acid sites

Recently, significant numbers of individuals with primary human immunodefic iency virus (HN) infection have been found to harbor viral strains with red uced susceptibility to antiretroviral drugs. In one study, HN from 16% of s uch antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5- a nd 10-fold lower than that of a wild-type control. Mutations in the RT doma in that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 var iable amino acid sites in RT for their effect on susceptibility and have id entified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sit es were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro m utagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.