This application proposes continuation of a broadly-based program for mentoring junior investigators in AIDS-related patient-oriented research. This proposal builds on existing resources of the Division of Infectious Diseases at Brigham & Women's Hospital, including an NIH-funded Adult AIDS Clinical Trials Unit, an Adult ACTG Virology Support Laboratory, the Harvard Medical School Center for AIDS Research, NIH-funded institutional AIDS training grants, and R01-funded research of the applicant. Clinical and research fellows as well as junior faculty interested in pursuing careers in retroviral therapeutics and translational virology will be mentored by the applicant. Course work in molecular biology, biostatistics, HIV-1 medicine, clinical trials design, responsible conduct of research and the ethics of human research will be offered. The research component of this proposal focuses on clinical investigation and formal clinical trials of HIV-1 therapeutics, drug resistance, and viral fitness. Ongoing patient-oriented research under the applicants direction comprises an array of studies with the overall goal of developing novel therapeutic approaches for the treatment of HIV-1 infection, and understanding the interplay between drug resistance, immune escape, and viral fitness. Specific research aims of this proposal are 1) to characterize CCR5 affinity, co-receptor tropism, and fitness of HIV-1 variants resistant to the CCR5 inhibitor SCH-417690 that emerge in subjects participating in a phase 2 trial of this drug (ACTG protocol A5211); 2) to characterize the fitness of immune escape mutants arising during the analytic treatment interruption phase of therapeutic vaccine trial (ACTG protocol A5197); and 3) to determine the influence of the HLA A*0201 allele on the rate of reversion of protease inhibitor resistance mutations in subjects interrupting a failing protease inhibitor. This research program provides a framework within which the applicant can mentor beginning clinical investigators in patient-oriented research focused on critical issues in HIV-1 medicine. ? ?
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