Surrogate markers are essential indices for the evaluation of treatment in a chronic, long-term, variably progressing illness like HIV infection. The major immunologic hallmarks of HIV infection are immune deficiency, immune activation, and specific immune response to HIV antigens. These have been related to the pathogenesis of HIV disease and to prognosis. The studies proposed here are directed at relating these immunologic surrogate markers to the effects of anti-retroviral and immune-based therapies (such as lymphokines, cytokine blockers and vaccines) and to treatment efficacy in ACTG protocols. Quantitative measurement of immune deficiency and activation will be done by three-color flow cytometry characterizing CD4 T cells, CD8 T cells, B cells, and NK cells. Functional assessments will include measurements of proliferation and cytotoxicity, as well as specific suppressor molecules. Levels of soluble serum markers and individual cytokines will be used to assess immune activation. Specific cell-mediated immunity will be tested by cytotoxicity against target cells expressing HIV proteins, which will be a critical immunologic marker for evaluation of vaccine trials as well as other treatment protocols in HIV-seropositive patients. The Developmental Immunology Research Program will work in conjunction with the Adult ACTU Core Program at UCLA and other institutions and SDAC to carry out these studies. Analysis are planned to compare effects of zidovudine, ddl and ddC and other compounds as they are developed. Data will be compared with CD4 (and CD8) T cell levels and p24 antigen and other virologic markers measured in associated studies. Surrogate markers will be evaluated to determine if a marker is changed by therapy, the maximum and duration of change and range of responses observed in HIV-infected persons. Also, surrogate markers will be compared head-to-head to determine whether they make distinctive or similar contributions to AIDS treatment evaluation. We will determine if additional surrogate markers can improve existing criteria indicating need for therapy. It is anticipated that eventually a small panel of surrogate markers will be able to provide essential and rapid evaluation of new agents, administration schedules and drug combinations.
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