Evidence of differential selection of HIV-1 variants carrying drug-resistant mutations in seroconverters

OBJECTIVES: To estimate the relative efficiency of transmission of different HIV-1 drug-resistance mutations from patients failing treatment, considered as potential transmitters (PTs), to seroconverters (SCs).

DESIGN: Ecological cross-sectional study.

METHODS: HIV-1 protease and reverse transcriptase (RT) sequence data, obtained from 155 SCs and 2,690 PTs at the Department of Molecular Biology of the University of Siena, Italy, in the period 1997-2004 were used. The efficiency of transmission was studied by odds ratio (OR) analysis and evaluation of 95% confidence intervals (95% CIs). For mutations not detected in viruses from SCs, a binomial probability model was used, assuming P-values <0.05 as indicative of a negative selection at transmission.

RESULTS: The overall prevalence of drug mutations associated with nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PIs) was 13.2%, 4.6% and 2.0% in SCs, and 69.9%, 27.6% and 33.7% in PTs, respectively. Among RT mutations present both in PTs and SCs, M1841/V and T215F/Y had the lowest relative efficiency of transmission, whereas V1181, Y181C/I and K219E/Q showed the highest relative efficiency. Of the three major protease mutations that could be evaluated by this approach, M46l/L had a lower rate of transmission than 184V and L90M. Among the mutations not detected in viruses from SCs, the RT E44D, V1081, Q151M and Y188C/H/L, and the protease D30N, G48V and V82A/F/S/T substitutions appeared to be negatively selected.

CONCLUSIONS: The transmission rate of drug-resistant HIV-1 variants may be differentially affected by the mutational pattern. The binomial model enabled to evaluate the negative selection against specific substitutions. Given the low prevalence of some resistance mutations in SCs, very large data sets are required to evaluate the potential selection of such mutations.