Targeting the HIV-1 Reservoir in Myeloid Cells

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ABSTRACT HIV is reverse-transcribed and integrated into the DNA of host cells, resulting in persistent infections that are difficult to clear. To date, there is no effective cure to clear the virus from HIV- infected patients. We have shown an approach to eradicate HIV infections by selective elimination of host cells harboring replication-competent HIV (SECH). The SECH treatment can clear HIV-1 in over 50% mice reconstituted with a human immune system, and in blood samples from HIV-1- infected patients. SECH can clear HIV-infection not only in CD4 T cells, but also in macrophages and microglia cells. Experiments are proposed to determine how to improve the efficacy and safety for SECH in clearing HIV-infection in the macrophage lineage: 1) To improve the efficacy and specificity in the killing of HIV-1-infected macrophages. We have found that increased viral reactivation leads to improved viral clearance in humanized mice. We will identify drugs that show greater potentials in virus reactivation that could lead to better HIV clearance. We will examine the inflammatory potentials for IDB and alternative LRAs in macrophages, and determine what inflammatory cytokines may need to be targeted; 2) To determine how to improve the efficacy and safety in the clearance of HIV reservoir in the macrophage lineage in lymphoid organs and in the brain of humanized mice. We will evaluate whether alternative agents can improve the clearance of HIV-1 in humanized mice in vivo. We will also determine whether optimum SECH regimens can induce limited and controllable inflammatory responses. Our proposed work will provide novel insights into how targeting apoptosis and autophagy regulates the clearance of HIV infection in the macrophage lineage. The studies will facilitate the development of SECH clear HIV-1 infection in lymphoid organs and in the brain to achieve complete eradication of HIV-1.