This is a proposal that evaluates the relationship between two CD4+ T cell destructive mechanisms, excessive alcohol consumption and HIV infection. Ethanol is believed to be a cofactor in HIV pathogenesis and both ethanol and HIV are known to cause the loss of T helper CD4+ lymphocytes leading to the impairment of multiple immune functions. Apoptotic cell death is a key mechanism involved in the depletion of CD4+ T lymphocytes during the HIV infection and is associated with an enhanced expression and subsequent triggering of the Fas receptor (FasR). Preliminary data from several experimental and clinical studies show that ethanol causes depletion of CD4+ T lymphocytes from peripheral blood, however, the mechanisms have not been characterized. The working hypothesis of this application is that alcohol consumption can be a cofactor in HIV pathogenesis by promoting enhanced oxidative stress and susceptibility of peripheral CD4 T lymphocytes to Fas-dependent apoptosis. Thus, the alcohol induced immunosuppressive effects should be attenuated by glutathione (GSH) enhancing prodrugs/precursors. The goals of this proposal are: 1) to elucidate the Fas-dependent mechanism involved in alcohol-induced immunosuppression and its role as a cofactor in HIV disease, and 2) to evaluate the efficacy of GSH enhancing prodrug/precursors N-acetylcysteine (NAC) and S-adenosyl methionine (SAMe) as possible therapeutic agents in counteracting alcohol and HIV infection mediated depletion of CD4+ T lymphocytes.
