N pallor, and perturbations in synaptic and dendritic density that may perhaps also include things like selective neuronal loss. The mechanism of HIV-mediated neurologic disorder is not entirely clear, however it is probably driven by both direct (active viral replication) and indirect sequelae to HIV invasion from the brain. Indirect mechanisms include dysregulation of glia, release of viral proteins, and elevation of neurotoxic proteins (TNF-, IL-6, IL-1, TGF-, endothelin, glutamate) from resident brain cells and infiltrating lymphocytes (11). The main targets of HIV infection inside the CNS are infiltrating monocytes/macrophages and microglia. Astrocytes constitute 400 of brain cells and deliver essential functions for brain homeostasis, like regulation of neuronal development, upkeep with the bloodbrain barrier, metabolism of neurotransmitters, secretion of neurotrophic elements, and immune surveillance in the brain by secretion of cytokines/chemokines (124). Astrocytes are CD4- but may perhaps express alternative receptors for HIV entry, such as D6, a promiscuous CCR (15), and mannose receptors, which may possibly assistance HIV entry by way of endocytosis and subsequent escape from endosomal vesicles (168). Despite the lack of clarity on how HIV enters astrocytes, our group previously demonstrated that astrocytes support productive HIV CYP11 Inhibitor Formulation replication if they are primed with IFN- prior to exposure to HIV (19). If IFN- is offered to astrocytes post-HIV infection, it will not market productive HIV replication, as well as the virus remains latent in astrocytes. Current research on postmortem tissue isolated from brains of HIV+ patients with neurocognitive impairment revealed considerable infection of astrocytes in vivo. Interestingly, the severity of HIV-associated dementia (HAD) correlated with the degree of HIV infection of astrocytes and their close proximity to perivascular macrophages (20). These studies suggested that below the acceptable environmental milieu, astrocytes can supportJ Immunol. Author manuscript; readily available in PMC 2012 June 15.Li et al.Pageproductive HIV replication. The mechanism by which signals, including IFN-, prime astrocytes for productive HIV replication is not clear. Astrocytes express robust levels of catenin signaling, which causes repression of HIV replication in astrocytes (21, 22) and PBMCs (23, 24). This CA I Inhibitor Formulation finding suggests a achievable interface between the -catenin pathway and the IFN- ignaling pathway that will impact HIV replication in astrocytes. The -catenin pathway is definitely the canonical pathway of Wnt signaling. It’s emerging as a crucial regulator of neurodegenerative ailments (258). The -catenin signaltransduction cascade is multifaceted and is described in detail elsewhere (29). Briefly, the canonical pathway is initiated by the binding of Wnt proteins (a family of 19 soluble secreted glycoproteins) to Frizzled (G-coupled seven transmembrane protein receptor, Fz) and low-density lipoprotein receptor-related protein 5 or six coreceptors. This event results in the inhibition of a multiprotein -catenin destruction complex (glycogen synthase kinase-3 [GSK3], axin, adenomatous polyposis coli, casein kinase 1), resulting in accumulation of a stable/hypophosphorylated -catenin. Active (hypophosphorylated) -catenin functions as a coactivator for T cell factor/lymphoid enhancer (TCF/LEF) transcription variables and, in conjunction with coactivators (CBP and p300), leads to target gene transcription. -catenin target genes effect cell differentiation, communication, apoptosis/surv.