The human immunodeficiency virus (HIV) has a unique tropism for cells expressing the CD4 antigen and virus-induced cytopathic effect in CD4- positive helper T-cells is a well established explanation for the immunodeficiency in late phases of the disease process. However, early after infection when numbers of helper T-cells are still within normal range, signs of immunodeficiency are already present and patients with similar reduction in the number of T-helper cells have differential susceptibility to opportunistic infections. The basis for this noncytopathic mechanisms of immunodeficiency is a major unexplained feature in the pathogenesis of HIV infection. The hypothesis of this proposal is that HIV infection of monocytes and T- cells results in and overexpression of transforming growth factor- beta(TGRbeta), one of the most potent endogenous immunosuppressive factors and that this defines a critical noncytotoxic pathway of immunodeficiency. This notion is supported by our recent findings that increased levels of TGFbeta are present in sera from HIV-infected patients and that it may account for the immunosuppressive activity previously described in these specimens. More importantly, blood mononuclear cells from HIV-infected donors produce increased levels of TGFbeta. Furthermore, we have demonstrated that TGFbeta preferentially inhibits proliferation of CD4+ cells and can thus contribute to the inversion of the CD4/CD8 ratio in HIV infection. The mechanism of regulation of TGFbeta expression in mononuclear phagocytes and T-cells is unknown. However, one potential pathway is suggested by our most recent data that the HIV accessory gene product tat can induce TGFbeta mRNA expression. We now plan to examine in detail (i) HIV-induced expression of TGFbeta at biochemical and protein level (ii) define cis-acting promoter elements in the TGFbeta; (iii) investigate the pathophysiological consequences of expression TGFbeta, and its receptors in HIV infected cells and (iv) study the clinical implications of TGFbeta production during the course of HIV infection. The results of these studies should lead to new insights on the biology of HIV, the means by which this virus induces expression of TGFbeta, and the role of this cytokine in the pathobiology of HIV- associated disease.
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