Recent WHO reports identify Mycobacterium tuberculosis (Mtb) as the single largest cause of death of individuals infected with the Human Immunodeficiency Virus (HIV), a co-infection state highly prevalent in Sub-Saharan Africa. Susceptibility to TB infection appears to be more complex than loss of surveillance through depletion of CD4+ T-cells. In preliminary experiments we show that replication of Mtb in macrophages is enhanced by co-infection with HIV. We propose extensive cellular and molecular analyses of experimental co- infections to be performed at Cornell University, Ithaca, NY. In addition, we have an HIV study cohort at the Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi and will probe the relevance of in vitro phenotypes through analysis of macrophages and lymphocytes from the lungs of HIV-infected individuals. This current study is founded on the hypothesis HIV infection of alveolar macrophages plays a significant role in the increased susceptibility to development of active tuberculosis.