The transmission of drug resistant HIV-1 represents a significant challenge to the public health as well as the treatment and prognosis of an HIV-1 infected individual. Treatment options for HIV-1 infection have evolved over the past 10 years such that many newly infected patients can be treated with as few as 2 pills taken once daily with acceptable short term and long term toxicities. However for many individuals simplified regimens are not an option due to the acquisition of drug resistant HIV-1. Furthermore, unlike drug resistant viruses in chronically infected individuals who discontinue therapy, transmitted drug resistant viruses persist in the newly infected host for years in the absence of treatment, increasing the risk of transmission to a susceptible host. Indeed, increases in the transmission of viruses resistant to one, two or even three classes of drugs have been documented over the past decade. The objectives of this proposal are three-fold;1. To continue to monitor for the prevalence of drug resistant transmissions with attention not only to traditional targets such as reverse transcriptase (RT) and protease (Pr), but to include newer drug targets such as viral envelope and integrase;2. To understand the potential for transmission of viruses resistant to inhibitors of RT, Pr and novels agents such as integrase inhibitors;3. To understand mechanisms by which MDR viruses compensate for mutations in RT and Pr, that confer high level resistance and yet allow for transmission. To accomplish these aims we will continue to identify newly HIV-1 infected individuals and use PCR technology to sequence relevant portions of the HIV-1 genome. Those viruses harboring drug resistant conferring amino acid substitutions will be tested for phenotypic resistance to specific agents. Using infectious molecular clones constructed from a panel of transmitted MDR HIV-1 viruses we will generate viruses resistant to integrase inhibitors by serial in vitro passage for in depth characterization with the underlying hypothesis that viruses with the potential for transmission must retain replication kinetics approximating that of wild type viruses. Finally, chimeric viruses will be constructed using infectious molecular clones to understand viral determinants by which MDR viruses compensate for predicted fitness loss thereby maintaining replication capacity, transmissiblity and pathogenicity.
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