Human immunodeficiency virus type I (HIV) invades the central nervous systems (CNS) early in infection and leads to neurological complications ranging from minor cognitive and motor disorders to HIV-associated dementia (HAD) in approximately 20-30% of infected individuals. Although the introduction of highly active antiretroviral therapy (HAART) has significantly decreased the incidences of HAD, the prevalence of neurocognitive/motor impairment is increasing as the HIV-positive population ages. Our laboratory has previously shown that the Wnt/Beta-catenin (canonical) pathway represses HIV replication in peripheral blood mononuclear cells (PBMCs) and astrocytes. The canonical Wnt pathway plays a neuroprotective role in the CNS and regulates many functions of neurons and glia, including growth, differentiation, and formation of synapses. We recently demonstrated that the HIV transcriptional transactivator (Tat), a potent neurotoxin, diminishes Wnt/Beta-catenin activity in neurons and astrocytes. This finding highlights a mechanism by which HIV evades the negative effects of Beta-catenin on its replicative cycle. In this project, we will test the hypothesis that down-regulation of Beta- catenin signaling in neurons and glia represents a novel mechanism by which Tat exerts its transactivation and neurotoxic effects. Using confocal microscopy to assess morphological changes, combined with conventional assays to evaluate apoptosis and chromatin immunoprecipitation (ChIP) studies to examine HIV LTR activity, we will determine the impact of altered Beta-catenin signaling on primary human neurons and astrocytes. We hypothesize that Tat-mediated antagonism of the canonical Wnt pathway will lead to a) dysfunctional synaptic activity and increased apoptosis of neurons and glia;b) enhanced release of pro-inflammatory cytokines and chemokines by resident brain cells;and c) increased HIV replication, partially as a result of removal of the downstream effector of the Wnt/Beta-catenin pathway, TCF-4, from the HIV LTR. These studies will describe a novel mechanism by which Tat promotes viral replication and promotes apoptosis of target brain cells and further highlights the role of Wnt/Beta-catenin as a neuroprotective pathway that combats both the direct (HIV replication) and indirect (inflammation, reduced cell survival) consequences of HIV infection in the brain. Greater understanding of the relationship between Beta-catenin signaling and HIV infection could lead to identification of new strategies to treat HIV infection in the CNS.
HIV causes neurologic dysregulation, characterized by impairment in neurocognitive function and/or motor skills in approximately 25% of infected individuals. The exact mechanism by which HIV mediates this impairment is not clear. This study will evaluate the relationship between HIV and a host signaling pathway (Beta-catenin) as they interface to impact HIV replication and pathogenesis in the brain. Greater understanding of the relationship between Beta-catenin signaling and HIV could lead to identification of novel strategies to treat HIV infection in the CNS.
|Narasipura, Srinivas D; Henderson, Lisa J; Fu, Sidney W et al. (2012) Role of *-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes. J Virol 86:1911-21|
|Henderson, Lisa J; Narasipura, Srinivas D; Adarichev, Vyacheslav et al. (2012) Identification of novel T cell factor 4 (TCF-4) binding sites on the HIV long terminal repeat which associate with TCF-4, *-catenin, and SMAR1 to repress HIV transcription. J Virol 86:9495-503|
|Henderson, Lisa J; Sharma, Amit; Monaco, Maria Chiara G et al. (2012) Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription through its intact core and cysteine-rich domains inhibits Wnt/Ã½Ã½-catenin signaling in astrocytes: relevance to HIV neuropathogenesis. J Neurosci 32:16306-13|
|Henderson, Lisa J; Al-Harthi, Lena (2011) Role of *-catenin/TCF-4 signaling in HIV replication and pathogenesis: insights to informing novel anti-HIV molecular therapeutics. J Neuroimmune Pharmacol 6:247-59|
|Li, Wei; Henderson, Lisa J; Major, Eugene O et al. (2011) IFN-gamma mediates enhancement of HIV replication in astrocytes by inducing an antagonist of the beta-catenin pathway (DKK1) in a STAT 3-dependent manner. J Immunol 186:6771-8|