A new mechanism of Treg cell dysfunction during HIV infection and propensity to oral cancer in people living with HIV

Abstract

Abstract Mechanisms of immune-dysfunction associated with chronic viral infections remain nebulous. Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV despite anti-retroviral therapy, but the underlying immune processes are poorly understood. Here we show an altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR− and inflammasome signaling, localized CD4+ T cell hyperactivation, and counterintuitively, enrichment of regulatory T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3+ cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR-2 ligands and IL-1β. Mechanistically, IL-1β upregulates PD-1 expression via AKT signaling and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving Asparaginyl Endopeptidase, resulting in FOXP3+ cells that are incapable of suppressing CD4+ T cells in vitro. Phenotypically similar cells are abundant in HIV-positive patients, and their presence strongly correlates with CD4+ T cell hyper-activation, suggesting diminished CD4+ T cell regulation in the oral mucosa in vivo. Taken together, this study provides unprecedented insights into the mechanism of FOXP3+ cell dysregulation and its potential role in mucosal dysfunction and cancer susceptibility in HIV patients. Supported by NIH NIDCR R01 DE026923