IFN-γ Mediates Enhancement of HIV Replication in Astrocytes by Inducing an Antagonist of the β-Catenin Pathway (DKK1) in a STAT 3-Dependent Manner

Typically, IFN-gamma is an antiviral cytokine that inhibits the replication of many viruses, including HIV. However, in the CNS, IFN-gamma induces HIV-productive replication in astrocytes. Although astrocytes in vitro are refractory to HIV replication, recent in vivo evidence demonstrated that astrocytes are infected by HIV, and their degree of infection is correlated with proximity to activated macrophages/microglia. The ability of IFN-gamma to induce HIV replication in astrocytes suggests that the environmental milieu is critical in regulating the permissiveness of astrocytes to HIV infection. We evaluated the mechanism by which IFN-gamma relieves restricted HIV replication in astrocytes. We demonstrate that although astrocytes have robust endogenous beta-catenin signaling, a pathway that is a potent inhibitor of HIV replication, IFN-gamma diminished beta-catenin signaling in astrocytes by 40%, as evaluated by both active beta-catenin protein expression and beta-catenin-mediated T cell factor/lymphoid enhancer reporter (TOPflash) activity. Further, IFN-gamma-mediated inhibition of beta-catenin signaling was dependent on its ability to induce an antagonist of the beta-catenin signaling pathway, Dickkopf-related protein 1, in a STAT 3-dependent manner. Inhibition of STAT3 and Dickkopf-related protein 1 abrogated the ability of IFN-gamma to enhance HIV replication in astrocytes. These data demonstrated that IFN-gamma induces HIV replication in astrocytes by antagonizing the beta-catenin pathway. To our knowledge, this is the first report to point to an intricate cross-talk between IFN-gamma signaling and beta-catenin signaling that may have biologic and virologic effects on HIV outcome in the CNS, as well as on broader processes where the two pathways interface. The Journal of Immunology, 2011, 186: 6771-6778.