A research program is proposed that will serve as the basis for mentoring beginning investigators in AIDS-related patient-oriented research. This proposal builds on existing resources of the Division of Infectious Diseases at the University of Colorado Health Sciences Center, including an NIH-funded AIDS Clinical Trials Unit, an Adult ACTG Virology Support Laboratory, the Colorado HIV-1 Medicine Training Program (funded by an Institutional AIDS Training Grant), and RO1-funded research of the applicant. Clinical and research fellows, as well as junior faculty, interested in pursuing careers in therapeutic AIDS clinical trials and translational virology will be mentored by the applicant. Course work in molecular biology, biostatistics, HIV-1 medicine, and the ethics of human research will be offered. The research component of this proposal is focused on clinical trials of HIV-1 therapeutics and drug resistance in HIV-1 infection. Ongoing patient-oriented research under the applicant's direction comprises an array of studies with the overall goal of understanding the mechanisms, clinical significance, and management of drug resistance in HIV- I infection. Specific research aims of this proposal are 1) to determine the relationship between drug resistance and treatment response in clinical trials of salvage therapy and treatment intensification conducted by the Adult ACTG.; 2) to compare the utility of genotypic and phenotypic approaches to drug resistance testing in the management antiretroviral therapy; and 3) To compare the relative fitness of HIV-1 carrying protease and reverse transcriptase genes from wild-type and drug-resistant clinical isolates using a novel recombinant virus assay. This research program provides a framework within which the applicant can mentor beginning clinical investigators in patient-oriented research focused on these critical issues in HIV-1 medicine.
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