HIV-1 replication in alveolar macrophages (SAM) and lymphocytes (AL) is thought to be actively restricted during clinical latency. With the onset of AIDS and the development of pulmonary infections there is an increase in both the number of HIV-1 repression in the lung have not been identified. Vitamin A and its metabolic derivatives (retinoids) have been shown to be potent regressors of HIV-1 expression in monocyte/macrophages. The lung normally contains significant levels of retinoids, however individuals with AIDS are compromised i their ability to maintain vitamin A homeostasis and are often vitamin A deficient. Levels of the CD8+ lymphocyte-derived cytokine, interleukin-16 are also elevated in the lungs of HIV-1 infected people. Significantly, IL-16 treatment of CD4+ T-lymphocytes represses the in vitro activation of HIV-1 LTR-directed expression. Experiments proposed in this application will determine whether retinoids and IL-16 can overcome HIV-1 activation by agents typically found i the lungs of AIDS patients (TNF-a, GM-CSF, IL-1b, IL-6, Mycobacterium tuberculosis, Pneumocystis carinii, Cryptococcus neoformans). Additional experiments will identify the cis=acting DNA elements involved in repression. The ability of retinoids to repress the ex vivo activation of HIV-1 in AM will be measured as a function of disease stage. The retinoid and IL-16 status of the lung will be evaluated and correlated with CD4+ and CD8+ T cell levels and disease progression. These experiments are part of the long term goal of both delineating he molecular mechanisms of retinoid and Il-16 mediated repression and determining the therapeutic potential of these agents.