Research is divided into studies concerning i) the phenotype, location and functional properties of the cells activated to produce specific antibodies and cytokines when stimulated with protein-based or plasmid DNA vaccines, ii) the nature of the immune responses induced by retrovirus infection of humans and mice and iii) the contribution of cytokine abnormalities to the pathogenesis of retrovirus-induced and autoimmune diseases. i) Cells were obtained from mice and humans immunized with purified recombinant HIV envelope glycoproteins and from mice immunized with plasmid DNA vaccines or synthetic oligonucleotides. The phenotype of the cells activated by each immunogen, and the magnitude, specificity and in vivo localization of the reactive cells, was studied. Both protein and DNA-based vaccines induced T cells to release type 1 cytokines. In contrast, type 2 cytokines were secreted by multiple cell types, including macrophages, FcR+ mast cells and T cells. Studies of synthetic oligonucleotides showed that unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrmidines contributed to the immune activation induced by these agents. ii) Two murine models of HIV infection are being examined. We found that MCMV infection interfered with ability of the murine AIDS virus to co-infect susceptible mice, such that the MCMV prevented the lethal sequelae of murine AIDs. In transgenic mice expressing gp120 proteins from HIV, the effect of immunization on tolerance induction and disease progression was investigated. In patients with HIV, changes in the frequency of type 1 and type 2 cytokine secreting cells was studied. Among freshly isolated PBMC, disease severity correlated with a loss of multiple types of cytokine secreting cells. The number of cytokine secreting cells in long-term non-progressors was stable. iii) We studied the number and antigenic specificity of B and T lymphocytes activated in patients and mice with SLE and AIDS. Results indicate that the pattern of cytokine activation is predictive of the nature and magnitude of the subsequent humoral response. Results indicate that the relative ratio (rather than absolute number) of Th1:Th2 type cytokine secreting cells correlates with disease progression. This ratio also appears to determine the relative frequency of IgG1:IgG2a secreting cells. In HIV-infected patients, monocytes were found to be major source of IL-6, IL-10 and TNFa, while T cells were the primary source of Th1 cytokines. Declining CD4 cell count correlated with a preferential loss of such Th1 secreting cells.
