TGF beta and HIV infection

TGF beta is a cytokine which is involved with the regulation of different aspects of host defense responses to injury. Overexpression of TGF beta can lead to the conversion of its protective functions to pathogenetic manifestations. TGF beta is a potent factor in promoting anabolic aspects in connective tissue metabolism, and uncontrolled production of TGF beta has been associated with the development of fibrosis. With respect to its effects on immune and inflammatory responses, TGF beta is an important endogenous immunosuppressive factor which physiologically may protect the organism from tissue damage caused by chronic activation of leukocytes. As a result of overproduction in HIV infection, this function of TGF beta can contribute to noncytopathic mechanisms of immunodeficiency. TGF beta is involved with several aspects of HIV disease and promotes virus replication and spreading through multiple distinct mechanisms. It directly stimulates virus replication in infected monocytes and peripheral blood mononuclear cells under certain in vitro conditions. It may stimulate the production of other cytokines that enhance virus replication and it may be the mediator of other HIV-stimulating agents such as cocaine. It enhances recruitment of mononuclear phagocytes as cells susceptible to virus infection. Through its profound and broad inhibitory effects on different antiviral defense mechanisms, it facilitates more rapid progression of virus infection and increases susceptibility to opportunistic infections and malignancies. Although these findings are largely based on in vitro systems, the demonstration of TGF beta overexpression in HIV-infected patients supports the notion that this cytokine is an important pathogenetic mediator in HIV infection and its associated diseases. Therapeutic strategies to interfere with these functions of TGF beta are the development of TGF beta-neutralizing antibodies and soluble TGF beta-binding proteins and receptors as well as approaches directed at reducing TGF beta gene expression.