The genetic diversity of HIV-1 in vivo allows the virus to surmount initially effective anti-viral drug therapies. Quasispecies under strong drug selection pressures will be genetically analyzed to better understand the emergence of drug resistance and to identify the major sites of virus replication. HIV-1 quasispecies developing viral protease inhibitor resistance will be examined at both the protease and envelope loci. The frequency of drug resistant variants before treatment and the impact of overall viral genetic diversity on drug efficacy will be determined. The genetic diversity of emerging drug resistant virus populations and the role of interloci recombination in generating genetic diversity (potentially a major impediment to combination drug efficacy) will be examined. A rapidly selected genetic marker (nevirapine drug resistance) will be used together with rapid and sensitive methods of genetic analysis to identify anatomical sites with the highest levels of viral replication. The lingering presence of drug sensitivity genetic markers will also be used to identify sites harboring long lived proviral reservoirs potentially capable of rekindling infection once therapy is discontinued. In order to allow frequent and extensive tissue collection RT-SHIV infected rhesus macaques will be used. The investigator believes that these experiments will identify the major anatomical sites of viral replication and establish the role of viral genetic diversity on drug efficacy.
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