Project 1: Transmission and Persistence of CTL and Drug Resistance MutationsFollowing 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 continuedpressures that selected for the mutation. Even mutations with significant cost in replication capacity may belost slowly when there is not wild-type virus already present to compete with the dominant viral variant Theoverall aims of this project are to determine whether there are selective pressures against the transmissionof certain drug resistance and CTL mutations, to determine predictors of time to loss of mutations, and toassess the effects of loss of mutations of HIV disease course.
These aims are important for advancing ourunderstanding of HIV transmission biology and early HIV pathogenesis, identifying optimal targets forvaccines designed to elicit protective CTL responses, and for developing strategies to limit the loss ofantiretroviral therapy options, particularly in developing countries. We will study approximately 160transmission partner pairs enrolled in the clinical core, and perform assessments of the persistence ofspecific mutations during longitudinal follow-up of newly infected partners and additional persons enrolled inearly HIV infection with mutations of interest. We will focus on gag and pol sequences, which encompasskey CTL epitopes as well as the region of drug resistance mutations. We will use a single cycle replicationassay developed by Monogram Bioscience using viral vectors including gag and pol sequences to measurechanges in replication capacity. We will test the hypothesis there are not substantial selective pressuresagainst transmission of virus due to the presence CTL or drug resistance mutations that are independent ofviral load in the source. We will follow-up newly infected persons who have acquired drug resistance andCTL escape mutations to determine predictors of time to reversion of mutations. We hypothesize thatgreater decreases in viral replication capacity associated with specific mutations will be an importantpredictor of shorter time to loss of the mutation. We will also test the hypothesis that loss of unnecessaryCTL escape mutations following HIV transmission will be associated with important increases in HIV viralload that will be proportional to the gain in viral replication capacity.
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