PROJECT SUMMARY Although combination antiretroviral therapy (ART) has led to significant HIV suppression and improvement in immune function, persistent viral reservoirs remain that are refractory to intensified antiviral therapy. However, ART poses many challenges such as adherence to drug regimens, the emergence of resistant virus, and cumulative toxicity as a result of long-term therapy. Moreover, these viral reservoirs directly or indirectly contribute to the rapid viral rebound that typically occurs within 2 weeks after cessation of ART. Thus, lifelong ART is required for continued viral suppression. Therefore, we need an effective approach that will eliminate HIV from viral reservoirs in individuals on suppressive ART. A number of novel far-reaching and varied therapeutic options are currently under investigation to address this concern, the most common of which is to eliminate the persistent CD4+ T cell viral reservoir. However, although latently infected CD4+ T cells are the predominant HIV reservoir, other cell types, such as macrophages and microglia also serve as sites of HIV persistence. These long-lived cells are resistance to the cytopathic effects of HIV and support persistent permissive HIV infection in the absence of CD4+ T cells. Moreover, they are resistant to CD8+ T cell-mediated killing. Therefore, we need an effective approach that will also eliminate HIV from these viral reservoirs in individuals on suppressive ART. However, in order to do this, it is essential that we understand how macrophage and microglia resist viral cytopathogenesis. Our preliminary data show that macrophages, in response to productive HIV infection, upregulate the expression of inhibitor of apoptosis proteins (IAPs) and triggering receptor expressed on myeloid cells-1 (TREM1), and that silencing or inhibition of these proteins promotes the selective death of HIV-infected cells without increasing viral replication. This suggests that (i) IAPs and TREM1 are responsible for myeloid cell resistance to HIV cytopathogenesis; and (ii) IAPs and TREM1 represent novel targets for the elimination of HIV. We therefore propose an innovative research program to: (i) conduct detailed mechanistic studies aimed at understanding how HIV-infected microglia resist viral cytopathogenesis with a focus on IAPs and TREM1; and (ii) identify new drug candidates that capitalize on these findings to reverse resistance and induce apoptosis of HIV- infected microglia without killing uninfected microglia. These studies are thus aimed at finding new effective approaches to curing HIV infection by eliminating persistent HIV infection from the myeloid reservoirs in ART- treated patients. This approach is fundamentally different from traditional strategies that target the virus itself, and we expect it to be complementary with ART. We also expect that the results from this work can be translated quickly into interventions aimed at eradicating HIV infection.