It has been a long-held view that the profound immunosuppression and lymphocyte destruction seen in HIV-1 infected patients takes place in the presence of a relatively modest viral burden. Recent observations which form the framework for this SPIRAT application clearly document the presence of an extensive plasma viral -burden. Application of aggressive anti-retroviral therapies can transiently reduce this burden by 2-3 orders of magnitude, only to have it re-establish with the emergence of drug resistance viral variants. If a greatly reduced viral burden could be maintained for prolonged periods of time, what impact would this have on the host immune response? Can the host begin to reconstitute lost functional immune reactivities or are additional measures such as thymic transplantation needed to assist a damaged lymphoid/stem cell compartment? These immunologic issues represent a major focus of studies proposed in Projects 1, 2, and 3 and tested within the context of the two Phase I clinical trials (i.e. SPIRAT Trials A and B). The principal overall goal, therefore, of the Cellular Immunology Core (Core II) is to provide standardized phenotypic and functional immunologic analyses of patient specimens generated by these trials. In order to perform realistic immunologic testing in association with these two highly complex clinical trials, a strategy was developed which was focused on only those measurements which could provide the most direct information regarding cellular function and phenotype. Throughout the trials, specimens will be archived in order to provide materials for more highly sophisticated testing in the context of future ancillary studies. With this in mind, our front line specific immunologic testing will include: l)two levels of immunophenotyping of whole blood specimens - a short panel for standard monitoring of CD4, CD8, NK, and B cells, and a long panel comprised of an extensive array of MoAb to be used in efforts aimed at determining the origin and maturation status of defined cellular subsets. 2)measurement of lymphocyte proliferation responses and collection/archiving of supernatants for future cytokine analyses, and 3)measurement of HIV- I specific CTL reactivities at the level of bulk activities as well as mature CTL and precursor CTL (CTLp) frequencies. Samples of PBMC and lymph node will be obtained and archived for future studies of TcR usage. Finally, the functional testing will be complemented by repeated skin testing, using a panel of defined recall antigens.
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