Canonical Wnts Mediate CD8⁺ T Cell Noncytolytic Anti–HIV-1 Activity and Correlate with HIV-1 Clinical Status

Abstract

CD8⁺ T cells do not rely solely on cytotoxic functions for significant HIV control. Moreover, the noncytotoxic CD8⁺ T cell antiviral response is a primary mediator of natural HIV control such as that seen in HIV elite controllers and long-term nonprogressors that does not require combined antiretroviral therapy. In this study, we investigated the biological factors contributing to the noncytotoxic control of HIV replication mediated by primary human CD8⁺ T cells. We report that canonical Wnt signaling inhibits HIV transcription in an MHC-independent, noncytotoxic manner and that mediators of this pathway correlate with HIV controller clinical status. We show that CD8⁺ T cells express all 19 Wnts and CD8⁺ T cell–conditioned medium (CM) induced canonical Wnt signaling in infected recipient cells while simultaneously inhibiting HIV transcription. Antagonizing canonical Wnt activity in CD8⁺ T cell CM resulted in increased HIV transcription in infected cells. Further, Wnt2b expression was upregulated in HIV controllers versus viremic patients, and in vitro depletion of Wnt2b and/or Wnt9b from CD8⁺ CM reversed HIV inhibitory activity. Finally, plasma concentration of Dkk-1, an antagonist of canonical Wnt signaling, was higher in viremic patients with lower CD4 counts. This study demonstrates that canonical Wnt signaling inhibits HIV and significantly correlates with HIV controller status.