Human Immunodeficiency Virus Type 1 (HIV-1) Transactivator of Transcription through Its Intact Core and Cysteine-Rich Domains Inhibits Wnt/β-Catenin Signaling in Astrocytes: Relevance to HIV Neuropathogenesis

Wnt/beta-catenin is a neuroprotective pathway regulating cell fate commitment in the CNS and many vital functions of neurons and glia. Its dysregulation is linked to a number of neurodegenerative diseases. Wnt/beta-catenin is also a repressor of HIV transcription in multiple cell types, including astrocytes, which are dysregulated in HIV-associated neurocognitive disorder. Given that HIV proteins can overcome host restriction factors and that perturbations of Wnt/beta-catenin signaling can compromise astrocyte function, we evaluated the impact of HIV transactivator of transcription (Tat) on Wnt/beta-catenin signaling in astrocytes. HIV clade B Tat, in primary progenitor-derived astrocytes and U87MG cells, inhibited Wnt/beta-catenin signaling as demonstrated by its inhibition of active beta-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt/beta-catenin signaling). Point mutations in either the core region (K41A) or the cysteine-rich region (C30G) of Tat abrogated its ability to inhibit beta-catenin signaling. Clade C Tat, which lacks the dicysteine motif, did not alter beta-catenin signaling, confirming that the dicysteine motif is critical for Tat inhibition of beta-catenin signaling. Tat coprecipitated with TCF-4 (a transcription factor that partners with beta-catenin), suggesting a physical interaction between these two proteins. Furthermore, knockdown of beta-catenin or TCF-4 enhanced docking of Tat at the TAR region of the HIV long terminal repeat. These findings highlight a bidirectional interference between Tat and Wnt/beta-catenin that negatively impacts their cognate target genes. The consequences of this interaction include alleviation of Wnt/beta-catenin-mediated suppression of HIV and possible astrocyte dysregulation contributing to HIV neuropathogenesis.