In HIV infection, the immune system is central in its role both as a protective organ and as a target of virus-induced pathology. Host recovery is dependent on the reconstitution of immune competence as well as the reduction or elimination of virus. Although antiretroviral therapy is essential to halt HIV progression, it may not be sufficient to treat the immunologic defects associated with disease. Based on the high correlation with disease prognosis and progression, changes in CD4 cell numbers have been monitored to reflect therapeutic benefit to the immune system during drug intervention protocols. However, recent findings indicate that the ability to use CD4 cell numbers as a marker of HIV disease activity is limited in the setting of prolonged antiretroviral therapy. To address the need for alternate disease-associated markers, we propose to serially monitor other vital components of immune response during ACTG phase II/III, antiretroviral protocols. Dual-antibody flow cytometry will be used to assess changes in the number and proportion of: 1) CD4 cell memory phenotype, CD45-RO; and 2) CD8 cell activated phenotypes, DR and CD38. Functional assays with isolated cell populations will be done to determine changes in: 1) CD4 cell, TH proliferative responses to recall antigens and mitogens; 2) CD8 cell, TS/C inhibition of autologous HIV replication; and 3) monocyte capacity to respond to activation stimuli, measured by expression of tissue factor and associated monokines. Measurements of HIV viral load will be done in parallel to assess correlations with disease activity and drug efficacy. Our research goals are: 1) to identify components of immunity that, independent of T cell number, reflect a positive immunologic response to antiviral therapy and; 2) to determine which impaired aspects of immune response require the addition of immune- based modulation therapy.
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