Fig 7. Integrated model of potential mechanisms of HIV transcription and latency modulation by β-catenin.

Schematic demonstrating multiple potential mechanisms by which β-catenin may modulate HIV transcription and latency, based on integrated findings from previous studies and data presented here. (1) β-catenin and TCF-4 form a complex with nuclear matrix-associated protein SMAR1 at the HIV LTR just upstream of the transcriptional start site and Sp-1, NFκB, and AP-1 binding sites. This complex pulls the HIV LTR towards the nuclear matrix, occluding access of RNA polymerase [35]. (2) β-catenin positively regulates levels of TCF-4, which has been shown to block binding and transcriptional regulation of NFκB at the HIV LTR [70]. (3) β-catenin further regulates c-Myc levels, which recruit HDAC enzymes, resulting in the viral promoter being more densely packed in chromatin [51]. (4) β-catenin also mediates self-renewal and cell proliferation of memory T cells through CBP, which may contribute to perpetuating the reservoir of latently infected cells [60], (5) A source of β-catenin signaling are CD8+ T cells, which secrete Wnt proteins resulting in stimulation of the Wnt/β-catenin pathway in CD4+ T cells, which culminates in accumulation of β-catenin in the cytoplasm and translocation to the nucleus [33]. This may explain the observed role of CD8+ T cells in maintaining HIV latency. Notably, other cells may serve as a source of Wnt proteins and β-catenin pathway modulating factors.