This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A significant increase in CD4 T cells occurs after the initiation of highly active antiretroviral therapy (HAART) in HIV-1 infected children. However, there are no large published studies in children delineating the dynamics of immune recovery in HIV-infected children during HAART. A multi-center study powered to examine the phenotype and function of T cells regenerated post - HAART initiation is needed to further assess several assumptions supported by the preliminary data. These preliminary data support the assumptions that 1) children with severe immunodepletion will develop significant numbers of CD4 T cells (particularly those of the naive phenotype) for 1-2 years after initiating HAART; 2) the recovery of T cells is dependent on a significant decrease in viral load in the first 3 months of therapy but does not require sustained suppression of viral replication after 6 months of therapy; 3) the spontaneous recovery of immunologic responses will not occur due to the clonal deletion of memory T cells; and 4) newly acquired CD4 T cells can develop responses upon antigenic exposure. This study will therefore examine the phenotype of T cells regenerated post initiation of HAART and assess their function by evaluating T cell responses to new antigens and recall antigens. One specific question to be addressed will be whether recovery of immunologic function in children occurs early in therapy when an increase in peripheral memory T cells is likely to occur. Alternatively, memory t cell clones may not be from expansion of peripheral memory T cells but rather may be derived from naive T cells that were recently educated to become memory cells. In order to further dissect function of newly generated T cells during HAART, cell mediated immune responses to a recall antigen (tetanus), a primary immunogen (hepatitis A) and an environmental antigen (Candida), will be tested. The ability of the newly generated T cells to respond to booster immunizations with tetanus toxoid and a new antigen T cell dependent antigen (hepatitis A).
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