This project was designed to investigate the cellular and molecular pathways involved in the HIV regulatory effects of cytokines/chemokines, tissue-associated factors and HIV envelope proteins. We had previously demonstrated that endogenous C-C chemokine receptor (CCR)-5-binding chemokines produced by CD4+ cells from asymptomatic HIV-infected individuals were found to play an important role in controlling in vitro replication of HIV strains that use CCR5 as an entry co-receptor. In contrast, CCR5- and CCR2-binding chemokines were found to enhance the level of endogenous HIV replication in CD4+ T cells of individuals at late stage HIV disease harboring X4 strains of HIV. Inflammatory cytokines and beta-chemokines acted cooperatively to enhance endogenous CXCR4 strain HIV replication, whereas these factors acted antagonistically in determining the level of endogenous R5 HIV strain replication. Our study of potential effects of chemokines on HIV replication are being expanded to include analysis of most C-C and CXC chemokines for their post-entry effects on HIV replication. Preliminary results suggest that numerous chemokines, such as SDF and RANTES, may influence post-entry HIV life cycle events, such as proviral integration. Following our previous in vitro observation that IL-2 and IL-15, but not IL-12, are potent inducers of CC chemokine production in lymphocytes, we have analyzed peripheral blood mononuclear cells from HIV-infected individuals receiving IL-2 subcutaneously. We have demonstrated that IL-2 administration in vivo results in increased CCR5 mRNA and intracellular protein levels, as well as in increased expression of CCR3 and CCR5 in the T lymphocyte population. Of interest, alterations in the susceptibility of PBMC to HIV infection in vitro were associated with IL-2 administration; however, these changes did not correlate with altered HIV CCR co-receptor expression.The ability of host factors or HIV envelope protein (gp160) to modulate HIV expression from cellular reservoirs of HIV, such as resting latently HIV-infected CD4+ T cells and macrophages isolated from HIV-infected subjects, was investigated. HIV gp160 was found to induce HIV expression from both cellular reservoirs of HIV. Induction of HIV from resting CD4+ T cells was not associated with expression of cellular activation markers, progression through the cell cycle, or interferon- gamma production. The fate of latently HIV-infected resting T cells stimulated to produce virus in this manner is being further investigated. In contrast, certain constitutive tissue associated factors, such as secondary lymphoid-associated chemokine (SLC) and the extracellular matrix protein tenascin, were found to suppress HIV expression from resting CD4+ T cells. These findings demonstrate that numerous lymphoid tissue-associated factors are capable of modulating HIV expression from cellular HIV reservoirs. - HIV; immunopathogenesis; cytokine; chemokine; lymphocyte; macrophage; HIV cellular reservoirs; envelope protein; extracellular matrix
