With 34 million people currently living with HIV, stopping the HIV epidemic remains imperative. Highly active antiretroviral therapy (HAART) limits viral replication, but is not curative. Thus, there is an urgent need to define and eliminate the viral reservoir. While the role of resting memory CD4+ T cells is well established, little is known about other cells as reservoirs. Macrophages are a major target of both HIV and SIV infection. They sustain viral replication in the absence of CD4+ T cells in vivo, have a significantly longer half-life than CD4+ T cells, and macrophage-derived virus is more infectious than CD4+ T cell-derived virus. These attributes make macrophages a likely source of latent virus and low-level viral replication during ART. Despite overwhelming evidence indicating the role of macrophages in viral persistence, no studies have directly assessed their role in the establishment and maintenance of viral reservoirs. Thus the central goals of our proposal are to define the contribution of macrophages to ongoing viral replication and pharmacologically deplete the macrophage reservoir. Cumulatively, these studies will define the importance of the macrophage reservoir, a critical hurdle that must be addressed in moving past HAART to a cure for HIV.