Viral load and CD4 T lymphocyte levels, generally applied prognostic measures of outcome to combination antiretroviral therapy, are insufficient measures to predict viral and immune response by many HIV-infected patients, particularly those who develop a discordant treatment responses. Selection of initial therapy is critical, as failure to suppress viral replication can lead to cross-resistance to alternative treatments. Complex combination therapies necessitate a more diverse repertoire of biomarkers with prognostic significance to guide design of optimal treatments for HIV infection among patients who are naive to protease inhibitors. The goal of the proposed clinical research is to identify novel biomarkers that have prognostic value for distinguishing viral and immune outcomes following initiation of antiretroviral therapy. Preliminary studies demonstrate a significant relationship between protease genotype and treatment outcome. The proposed research will address two hypotheses: that natural genetic polymorphisms in protease provide prognostic markers for viral and immune outcomes to combination therapy in immune suppressed patients, and that viral genetic determinants in addition to protease and/or host factors provide novel prognostic measures of treatment outcome for patients who show CD4 T cell reconstitution despite a resurgence in virus levels. To test these hypotheses, four specific aims have been designed to evaluate: l. a relationship between naturally occurring amino acid polymorphisms in HIV-1 protease, reverse transcriptase, and gag, and response to combination antiretroviral therapy; 2. prognostic significance of changes during 24 weeks of therapy in viral genotype and phenotype, as measured by changes in co-receptor usage and replication in macrophages, to outcome in patients who display immune reconstitution and high viral burden in response to therapy; 3. relationship between capacity for immune reconstitution, as measured by molecular analyses of TCR repertoire in CD45RA and CD45RO subsets, and treatment outcome; and 4. changes after 24 and 48 weeks of therapy in viral genotype, phenotype, and extent of immune reconstitution as intermediate markers for disease progression. The research design is a longitudinal, cohort study of 120 HIV-infected children and adolescents, untreated with protease inhibitors, with high viral levels, and suppressed CD4 T cell counts. The multivariate approach will identify novel biomarkers that lead to design of improved, individually tailored protocols to initiate therapy for patients infected by HIV- 1.
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