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

Abstract

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

FIG. 1

Phylogenetic tree of RT sequences from patients with primary HIV infection. An unrooted maximum-likelihood phylogenetic tree for all 110 sequences analyzed is shown. The two outgroup sequences at the base of the tree belong to HIV-1 subtype C; all others are subtype B. Bootstrapped neighbor-joining trees gave essentially the same topology, and the number of bootstrap resamples supporting internal clusters (out of 1,000) is shown for all cases above 500. Symbols represent virus with wild-type (○) and reduced (●) susceptibility to NNRTI in the PhenoSense HIV assay. IC50, 50% inhibitory concentration.