HIV reverse-transcriptase drug resistance mutations during early infection reveal greater transmission diversity than in envelope sequences.

Background: Drug resistance mutations (DRMs) can serve as distinct, nonpolymorphic markers for evaluating diversity of expressed HIV-1. We screened for DRMs during early-acute viremia and examined the diversity in reverse transcriptase (RT) relative to envelope (env) in cases of transmitted drug resistance.

Methods: We evaluated 111 longitudinal plasma samples collected every 2-7 days from 15 individuals who seroconverted for HIV-1 infection in 1994-2000. The samples were screened with sensitive polymerase chain reaction assays for the commonly transmitted M41L and K70R mutations and for K65R, which was undetected by bulk sequencing. Mutation-positive samples were further characterized by clonal sequencing of RT and env V1-V3.

Results: Drug resistance mutations were detected in 4 of 15 seroconverters at 5-50 days of viral nucleic acid expression; most mutations disappeared about the time of seroconversion. Clonal sequencing verified low-level K65R at frequencies of 0.4%-4.9%. In each case, K65R coexisted unlinked with variants carrying 2-5 thymidine analog mutations at frequencies of 1.6%-23.0%. In one seroconverter, variants with M184V and nonnucleoside RT inhibitor mutations were also identified at first RNA expression. Each seroconverter displayed a homogeneous V1-V3 env population.

Conclusions: Reverse-transcriptase DRMs demonstrate that the breadth of variants in transmission may be greater than what is reflected in envelope sequences.