Project 1: Transmission and Persistence of CTL and Drug Resistance Mutations Following HIV transmission, mutations that evolved in the earlier host to evade cytotoxic T-lymphocyte (CTL) and antiretroviral drug pressures may persist for long periods of time despite the absence of continued pressures that selected for the mutation. Even mutations with significant cost in replication capacity may be lost slowly when there is not wild-type virus already present to compete with the dominant viral variant The overall aims of this project are to determine whether there are selective pressures against the transmission of certain drug resistance and CTL mutations, to determine predictors of time to loss of mutations, and to assess the effects of loss of mutations of HIV disease course.
These aims are important for advancing our understanding of HIV transmission biology and early HIV pathogenesis, identifying optimal targets for vaccines designed to elicit protective CTL responses, and for developing strategies to limit the loss of antiretroviral therapy options, particularly in developing countries. We will study approximately 160 transmission partner pairs enrolled in the clinical core, and perform assessments of the persistence of specific mutations during longitudinal follow-up of newly infected partners and additional persons enrolled in early HIV infection with mutations of interest. We will focus on gag and pol sequences, which encompass key CTL epitopes as well as the region of drug resistance mutations. We will use a single cycle replication assay developed by Monogram Bioscience using viral vectors including gag and pol sequences to measure changes in replication capacity. We will test the hypothesis there are not substantial selective pressures against transmission of virus due to the presence CTL or drug resistance mutations that are independent of viral load in the source. We will follow-up newly infected persons who have acquired drug resistance and CTL escape mutations to determine predictors of time to reversion of mutations. We hypothesize that greater decreases in viral replication capacity associated with specific mutations will be an important predictor of shorter time to loss of the mutation. We will also test the hypothesis that loss of unnecessary CTL escape mutations following HIV transmission will be associated with important increases in HIV viral load that will be proportional to the gain in viral replication capacity.
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