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. HIV-1 infected children treated with multiple potent antiretrovirals have experienced a significant increase in CD4 T cells after the initiation of highly active antiretroviral therapy (HAART). Although researchers are aware there are several changes in the immune function following HAART, no large published studies have delineated the dynamics of immune recovery in HIV-infected children. Adults treated with HAART have had mean increases of 250 CD4 T cells/uL and the return of some T-cell mediated responses to recall antigens (1). This return of functional memory T cells may be due to the fact that the majority of the replenished T cells are of the 'memory' phenotype, perhaps elicited by proliferation of peripherally distributed T cells, and presumably independent of recent thymic education (2). This increase in memory CD4 T cells is similar to that seen in adult cancer chemotherapy patients who have a recovery of exclusively memory cells after T cell depletion (3). In addition, Connors et al. reported that the phenotype of T cell regenerated after the initiation of HAART depends on the types of T cells present before therapy despite robust increases in CD4 cell counts (4). The role of the independent thymic pathway in the regeneration of the immune system to a near normal level post- HAART seen in adults may not coincide with the process occurring in children. In contrast, the age dependent thymopoietic pathway may be the catalyst for the regeneration of a normal and sustainable diversity of CD4 T cell repertoire. Thymic enlargement during HAART treatment was recently observed in a small study of HIV-infected children suggesting an active role of the thymus in this population (5). Understanding the pathogenesis of T cell recovery in HIV-infected children and to what extent there is restoration in the ability of the immune system to respond to recall and neo-antigens will impact on the clinical management and ultimately on the survival of these patients. These findings will define the role of vaccines and chemoprophylaxis in disease prevention in these patients. These preliminary data support the assumptions that 1) children with severe immunodepletion will develop significant numbers of CD4 T cells (particularly those of a 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 not on the sustained inhibition 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 to antigens encountered. 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. The objectives of this study are:1) To assess the ability of newly derived CD4 T cells to spontaneously develop lymphoproliferative responses to a recall antigen, tetanus toxoid, or to develop responses after booster vaccinations with tetanus vaccine, 2) To assess the ability to develop protective antibody responses to a T cell dependent antigen using a primary series of hepatitis A vaccinations; 3) To measure the durability of any response beyond the last vaccination. Secondary objectives are: 1) To measure CD4 T cell percentage at baseline and at the time of vaccination(s) and to correlate these with the establishment of immune responses; 2) To study the correlation of the establishment of phenotypic 'naive' and 'memory' T cells at baseline and the time of vaccination(s) with the establishment of immune responses; 3)To assess the ability of newly-derived CD4 T cells to develop spontaneous cell-mediated immune responses to an environmental antigen, candida; 4) To assess the ability to develop lymphoproliferative responses to T cell-dependent antigen, hepatitis A; 5)To assess whether the recovery of functional immunity is seen early or late after HAART; 6)To measure the HIV plasma copy number at baseline, the time of vaccination(s), and at the study completion (104 weeks) and to correlate these with the establishment of immune responses; 7)To assess the safety of giving multiple immunizations with FDA licensed vaccines to HIV-infected children and young adults; and 8)To assess whether a hepatitis A vaccination booster at week 100 will result in an increase in hepatitis A antibody.
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