Wnt/beta-Catenin Protects Lymphocytes from HIV-Mediated Apoptosis via Induction of Bcl-xL

HIV infection mediates the apoptosis of lymphocytes, the mechanism of which is multi-faceted. Here, we evaluated the role of Wnt/beta-catenin signaling in HIV-associated T cell apoptosis, as Wnt/beta-catenin regulates the transcriptional activity of genes impacting apoptosis. We specifically investigated the role of the Wnt/beta-catenin pathway in the HIV-associated apoptosis of CD4+ T cells and CD4(dim)CD8(bright) T cells, a population that is infected by HIV We found that the induction of beta-catenin, via a 6-bromoindirubin-3-oxime (BIO), significantly rescued HIV-infected CD4+ and CD4(dim)CD8(bright) T cells from apoptosis by >40-50%. Further, a small-molecule inhibitor of the Wnt/beta-catenin pathway (PNU-74654) reversed BIO-mediated protection from HIV-associated apoptosis. BIO also induced Bcl-xL, an anti-apoptotic protein, and a target gene of Wnt/beta-catenin, in CD4+ and CD4(dim)CD8(bright) T cells by approximately 3-fold. Inhibiting Bcl-xL by WEHI-539 abrogated beta-catenin-mediated apoptotic protection in infected CD4+ and CD4(dim)CD8(bright) T cells. Collectively, these findings demonstrate that engaging Wnt/beta-catenin signaling in HIV-infected T cells protects them from HIV-associated apoptosis by inducing Bcl-xL.