Acute and chronic alcohol abuse alters many specific immune functions and has been implicated as a cofactor in HIV/AIDS disease. Our overarching hypothesis is that alcohol affects HIV infection of human immune cells through modulation of the function of the cells, including microglia, macrophages and T cells that are primary targets for HIV in the blood tissues and central nervous system (CNS). We will use immune cells isolated from healthy donors and from HIV-infected individuals with and without alcohol abuse to investigate these relationships. We will explore whether chronic alcohol abuse increases immune cell susceptibility to the HIV infection and determine whether chronic alcohol use by HIV-infected individuals increases HIV replication and leads to events that could promote HIV disease progression. We will investigate four specific aims: 1) we will determine whether alcohol affects the expression of HIV receptors (CD4, CCR3, CCR5 and CXCR5), production of beta-chemokines (RANTES, MIP-1alpha and MIP-1beta), and cytokines in immune cells derived from healthy individuals; 2) we will determine whether alcohol, through alteration of the functions of the immune cells, modulates replication of HIV in macrophages (including microglial cells) and CD4+ T lymphocytes. We will study effects of alcohol on HIV entry, viral replication and the molecular mechanism of alcohol-mediated HIV replication in macrophages, including viral entry, transcription and LTR promotor; 3) we will determine whether alcohol has the ability to activate and enhance HIV replication in latently infected immune cells; and 4) we will measure the levels of HIV RNA and beta-chemokines (MIP-1alpha, beta and RANTES) in the plasma from HIV-infected patients with or without alcohol abuse. We also will use peripheral blood mononuclear cells (PBMCs) from these subjects to analyze the expression of HIV co-receptors and numbers and ratio of T cell subsets. We will isolate PBMCs to determine the effect of chronicalcohol dependence on recovery of latent HIV. These studies may provide new mechanistic insights related to the role of alcohol in the pathogenesis of HIV disease and AIDS and toward design of new therapeutic approaches.