Interplay between Wnt/β-catenin signaling and HIV: virologic and biologic consequences in the CNS

Abstract

Considerable studies have evaluated the interaction between Wnt/β-catenin signaling and numerous cellular processes. Emerging findings now demonstrate that Wnt/β-catenin signaling interacts with the life cycle of the Human Immunodeficiency Virus type 1 (HIV-1). Wnt/β-catenin is a restrictive pathway to HIV replication in multiple target cells including peripheral blood mononuclear cells and astrocytes. The molecular interaction between Wnt/β-catenin signaling and HIV has been evaluated in astrocytes because they express robust level of this pathway. The cross talk that occurs between these two components has significant biologic consequences to HIV-mediated neuropathogenesis. This perspective highlights current knowledge regarding the interaction between Wnt/β-catenin signaling and HIV, the interplay between these two pathways as it impacts key features of NeuroAIDS, and provides an assessment of knowledge gaps in the field that could propel our understanding of this interaction to inform novel strategies to exploit Wnt signaling for therapeutic intervention in HIV/NeuroAIDS.

Figure 1. Wnt/β-catenin signal transduction pathway

Wnt protein binding to seven transmembrane Frizzled receptors leads to the recruitment of Axin to the plasma membrane and phosphorylation of its co-receptor, low-density lipoprotein receptor related protein (LRP) 5/6 by casein kinase-1α (CK1α) and glycogen synthase kinase-3β (GSK3β), leading to activation of Dishevelled (Dvl) and destabilization of a β-catenin destruction complex. The destruction complex consists of Axin, adenomatous polyposis coli (APC), CK1α and GSK3β. Hypophosphorylated β-catenin accumulates in the cytoplasm and is able to translocate to the nucleus, where it interacts with TCF/LEF to displace its co-repressors and recruit either positive or negative transcription co-factors to regulate Wnt target genes. Active β-catenin can also bind to cadherins at the cell membrane to regulate cellular adhesion. In the absence of Wnt binding to frizzled and LRP5/6, cytosolic β-catenin is phosphorylated by the destruction complex and undergoes βTrcp-mediated ubiquitination and proteasomal degradation. Image is slightly modified and reprinted from (Henderson and Al-Harthi, 2011), copyright © J Neuroimmune Pharmacology [(2011) 6: 247-259, DOI: 10.1007/s11481-011-9266-7].

Figure 2. Mechanism of β-catenin/TCF-4-mediated suppression of basel LTR activity

β-catenin/TCF-4/SMAR form a complex at −143 site of the HIV LTR .This multiprotein complex pulls the HIV DNA spanning this region into nuclear matrix and away from transcription machinery. Inhibition of β-catenin/TCF-4 disrupts this chromatin repression complex and allows for POLII docking and recruitment of transcription co-activators (TCoA) such as NFκB and C/EBP to drive basal LTR activity. Therefore, signals that inhibit β-catenin/TCF-4 signaling are likely to induce HIV transcription by disrupting this inhibitory complex. This image is a reprint (Henderson et al., 2012b), Copyright © American Society for Microbiology, [Journal of Virology, Vol. 86 no. 17 9495-9503, 2012, DOI: 10.1128/JVI.00486-12].

Figure 3. Mechanism of Tat/β-catenin interaction in astrocytes

β-catenin and TCF-4 repress basal and Tat transactivation of the HIV LTR through distinct mechanisms and are in turn antagonized by HIV Tat. (a) Under basal LTR activity (without significant Tat level), the TCF-4/ β-catenin/SMAR1 complex represses LTR activity and transcription is low or silent. Low levels of Tat may be produced but are primarily retained in the cytoplasm by association with TCF-4. (b) When β-catenin signaling is disrupted by pro-inflammatory mediators (IFNγ) or any other signal that down regulates the β-catenin pathway, this complex is disrupted and LTR activity increases. Once the level of Tat reaches a certain threshold, Tat will a) transactivate the HIV LTR by inducing chromatin remodeling and recruiting positive transcription elongation factor b (pTEFb), allowing for efficient viral replication; and b) antagonize β-catenin signaling through mutual binding/inhibition with TCF-4 and enhanced degradation of β-catenin to maintain a permissive state for HIV replication. The broader biological consequences of productive infection in astrocytes include raising the CNS viral load and increasing production of neurotoxic HIV proteins (Tat, gp120, Vpr), potentially leading to neuronal injury and neuroinflammation. The image is a reprint (Henderson et al., 2012c), Copyright © Society of Neuroscience, [Journal of Neuroscience, in press, doi:10.1523/JNEUROSCI.3145-12.2012].

Figure 4. Current model of effects and consequences of diminished β-catenin signaling in the CNS

Astrocytes express robust level of β-catenin signaling. Inflammatory signals that diminish β-catenin signaling in astrocytes, leads to enhanced HIV transcription and productive HIV replication in astrocytes. The consequence of these events include higher level of HIV in the CNS, release of cell permeable HIV neurotoxins, heightened overall inflammation, and dysregulation in astrocyte function, most notable of which is inhibition of EAAT2 and glutamate uptake by astrocytes. Dysregulated astrocytes will result in dysregulated cross talk with neurons that will in turn impact key events in neuronal health, including neurogenesis (which is partly mediated by Wnt ligands events and synaptogenesis, which are partly mediated by Wnt ligands, culminating in neurodegenerative processes (e.g dendritic pruning and synaptic damage).