β-catenin regulates HIV latency and modulates HIV reactivation

Latency is the main obstacle towards an HIV cure, with cure strategies aiming to either elicit or prevent viral reactivation. While these strategies have shown promise, they have only succeeded in modulating latency in a fraction of the latent HIV reservoir, suggesting that the mechanisms controlling HIV latency are not completely understood, and that comprehensive latency modulation will require targeting of multiple latency maintenance pathways. We show here that the transcriptional co-activator and the central mediator of canonical Wnt signaling, beta-catenin, inhibits HIV transcription in CD4+ T cells via TCF-4 LTR binding sites. Further, we show that inhibiting the beta-catenin pathway reactivates HIV in a primary T-CM cell model of HIV latency, primary cells from cART-controlled HIV donors, and in CD4+ latent cell lines. beta-catenin inhibition or activation also enhanced or inhibited the activity of several classes of HIV latency reversing agents, respectively, in these models, with significant synergy of beta-catenin and each LRA class tested. In sum, we identify beta-catenin as a novel regulator of HIV latency in vitro and ex vivo, adding new therapeutic targets that may be combined for comprehensive HIV latency modulation in HIV cure efforts. Author summaryThere is no cure for HIV despite over 30 years of research. An HIV cure will rely on understanding cellular pathways that regulate HIV latency, which can be exploited for cure strategies. We report here for the first time that transcriptional co-activator beta-catenin regulates HIV latency in the primary target for HIV latency, the CD4+ T cell population. We also show that its manipulation can reactive or repress HIV alone or in combination with known modulators of HIV latency. Together, our findings classify beta-catenin as a regulator of HIV latency with significant applications to cure strategies.

Automated summary

Latency is the main obstacle towards an HIV cure, and targeting multiple latency maintenance pathways is essential. In this study, beta-catenin, a transcriptional co-activator and central mediator of Wnt signaling, is identified as a regulator of HIV latency. Inhibiting or activating the beta-catenin pathway can reactivate or repress HIV, and it also enhances or inhibits the activity of other HIV latency reversing agents.