Neurological disorders associated with HIV-1 affect 40-70% of infected individuals and is characterized as HIV- 1-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) has diminished disease severity, milder forms of cognitive impairment remain commonplace. It is critical to discover new therapeutic strategies to fully prevent the neurocognitive impairment. Active neurogenesis occurs throughout life and relies upon the proliferation, migration, and proper differentiation of neural stem/progenitor cells (NPCs). Under pathological conditions of the central nervous system (CNS) associated with neuroinflammation such as HAND, monocytes/macrophages infiltrating the CNS in concert with activated resident microglia play a major role in the neurodegenerative process of HAND. Activated macrophage/microglia produce inflammatory mediators such as cytokines and chemokines, affect the capacity of brain stem cells and alter neurogenesis. Various types of macrophage/microglia activation, depending on the conditions, can either enhance or suppress neurogenesis. Inflammation-associated M1 macrophages/microglia can inhibit neurogenesis;whereas IL-4-activated M2 macrophages/microglia can induce both neurogenesis and oligodendrogenesis. In HAND, HIV-1 infection in the brain inhibits neurogenesis with generation of fewer adult NPCs in the dentate gyrus of the hippocampus. Moreover, NPCs preferably differentiate into astrocytes rather than neurons. Our previous studies demonstrated HIV-1-infected and LPS-activated (M1) Macrophages inhibit neurogenesis, while enhancing gliogenesis through secretion of inflammatory cytokines such as IL-1? and TNF-?. microRNA- 124 (miR-124) has recently been shown to deactivate M1 macrophages and skew their polarization from an M1 toward an M2 phenotype. miR-124 may serve as a useful tool to transfer detrimental pro-inflammatory M1 macrophages/microglia to beneficial M2 macrophages/microglia. Therefore, we propose the following specific aims:
Aim 1 : To investigate how miR-124 deactivates HIV-1-infected M1 macrophages/microglia or polarizes them to an M2 phenotype and promotes neurogenesis in vitro.
Aim 2 : To investigate the therapeutic potential of miR-124 for ameliorating HIV-1-infection-mediated inhibition of neurogenesis in HIV-1 encephalitis (HIVE) and humanized mouse models. We will test our hypothesis using primary human NPC, macrophage/microglia culture systems, and HIVE and humanized mouse models. This novel system mimics the HIV-1-infection and immune-activation of brain macrophage/microglia as they occur within the CNS during HAND. We will validate the effect of miR-124 on modulating macrophage/microglia activation and its subsequent effect on neurogenesis in vitro and in vivo. The data generated from this study will help to identify a highl innovative strategy for HAND therapy. Furthermore, these findings will provide insight into a range of other neurodegenerative and neuroinflammatory diseases in which macrophage/microglia activation plays an important role.
HIV infection of the central nervous system can result in HIV-1-associated neurocognitive disorders (HAND), while neural stem cell dysfunction may contribute to disease pathogenesis. This proposal is aimed at understanding the molecular mechanisms that regulate neurogenesis in HAND and testing the therapeutic potential of microRNA-124 for ameliorating disrupted neurogenesis.