Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs

Abstract: HIV cure has not been achieved due to long-lasting latent HIV reservoirs that, upon ART interruption, reactivate the virus. The best characterized viral reservoirs are different circulating subpopulations of T lymphocytes, but it has become evident that most viral reservoirs are localized in several tissues, including the brain. However, little is known about HIV persistence in myeloid cells, becoming a controversial issue. Only recently, genetic phylogenetic analysis indicates that viral reactivation cannot be explained by CD4 T containing the virus. Thus, alternative reservoirs need to be considered, such as a myeloid cell. Myeloid tissue-associated cells have multiple advantages over T cells to consider long-lasting viral reservoirs including tissue location, long-life, slow turn around, and higher resistance to apoptosis compared to T cells. In the brain, microglia and macrophages are the main cell type with HIV-integrated. Our data identify macrophage/microglia as a key viral reservoir within the brain, even in long-term ART. We developed an in vitro system to generate latent infected microglia or macrophages that can be reactivated by multiple treatments, including Meth, LPS, and LRA. The latently HIV-infected macrophages/microglia cells survive infection by blocking the apoptosome's formation by increasing bim protein expression, preventing further apoptosis. Further, we identified that latently HIV-infected cells (microglia/macrophages) had a unique metabolic signature that relies on glutamate/glutamine for ATP production and survival. More surprising is that HIV reservoirs cannot switch between different carbon sources such as lipids, glucose, or unusual sources of carbon like amino acids like uninfected cells. Blocking these metabolic pathways results in significant apoptosis of HIV reservoirs even in the absence of reactivation. Our results will provide a better understanding of the mechanisms that regulate the generation and survival of HIV myeloid reservoirs within the CNS and provide essential information for eradicating these viral reservoirs from the CNS.