ABSTRACT Residual oral inflammation along with chronic systemic immune activation is an important feature in many (HIV)/Combined Antiretroviral therapy (cART) patients, and has been linked to a wide range of oral pathologies including periodontitis, erythematous candidal lesions, viral infections and oral cancer. Although cART can suppress plasma viral loads to undetectable levels, increased mortality is closely associated with mucosal immune dysbiosis and persistent viral reservoirs in lymphoid tissues. To date, however, the majority of research on immune activation has been derived from analysis of circulating quiescent T cells. How microbial products from altered oral microbiome and opportunistic pathogens contribute to immune cell alterations and oral mucosal dysbiosis is unknown. A better comprehension of this phenomenon, and various interactions between immune cells, commensal and pathogenic microbes is needed to shed light on HIV-mediated immune oral immune dysfunction. Our proposal will investigate these interactions with a specific focus on Th17 cells and Tregs, the critical subsets of CD4+ T lymphocytes that play crucial roles in maintaining the mucosal barrier integrity and preventing inflammation respectively. We hypothesize that loss of oral Th17 cells and increase in proportions of dysfunctional Tregs contribute to residual oral inflammation in HIV+ patients. We will determine the functions of interventional IL-21 in restoring Th17 cells during HIV infection. We will also define the role of TLR signaling and IL-6 in inducing Treg plasticity, generating dysfunctional Tregs and contributing to oral immune pathogenesis of HIV+ individuals. These studies will contribute to new ways of thinking about oral inflammation in HIV+ individuals, and aid in generating novel therapeutic strategies to manage HIV mediated chronic oral dysbiosis. This multidisciplinary project supported by a robust procurement network for human tonsillar and oral tissues from HIV+ individuals will enable an unprecedented insight into HIV dependent oral mucosal inflammatory mechanisms, and is compatible with Trans-NIH FY-2016 funding priorities for HIV research that states “Study the effect of the CD4+ T-cell pool heterogeneity in terms of differentiation .. lineage (Th1, Th2, Th17, Treg, Tfh), anatomic location (blood versus lymphoid tissues versus mucosal tissues)”, as area of research priority. Most importantly, by defining the immune plasticity mechanisms in Th17 cells and Tregs during HIV+/SIV infection, the project fits well with the program objectives for RFA-DE-17-006.