Innate immune mechanisms of epithelial barrier disruption during treated HIV and SIV infections

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PROJECT SUMMARY Antiretroviral therapy (ART) has led to a paradigm shift from HIV infection being a fatal disease to a manageable chronic illness. People living with HIV (PWH), however, are plagued with incomplete immune restoration, increased intestinal dysfunction, residual inflammation, and high prevalence of non-infectious comorbidities such as metabolic, cardiovascular, kidney, and liver diseases. Given the evidence of intestinal epithelial barrier damage (IEBD) and microbial translocation (MT) driving HIV-associated inflammation, and the link between chronic inflammation and non-infectious comorbidities in PWH, better understanding of the gut- mediated immune mechanisms underlying the process of IEBD and inflammation during long-term treated HIV infection is critical. Our preliminary studies demonstrate a synergy between innate gdT cells and Innate Lymphoid Cell type 3 (ILC3) dysfunction during long-term cART in the SIV-macaque model. Further, we recently reported that a loss in epithelial barrier protective IL-17/IL-22 functions of Vd2 gdT cells may contribute to IEBD and MT and resultant systemic inflammation during long-term SIV-ART. Based on this, we propose to test the hypothesis that specific dysregulation of IL-17/IL-22 pathway in Vd2 gdT cells and ILC3 leads to breakdown of tight junctions of the gut epithelial barrier, resulting in MT and systemic inflammation during chronic HIV infection with long- term ART. Toward this goal, we aim to longitudinally assess the transcriptional and immunophenotypic signatures of Vd2T and ILC3 cells and evaluate gut barrier functions in different sections of the GI tract through the course of long-term ART in SIV infection. Second, we will test the hypothesis that in vivo activation of Vd2T cells will restore gut barrier integrity and reduce inflammation during long-term SIV-ART via enhanced IL-17/IL- 22 function. Toward this, we will administer the Vd2T-stimulating amino-bisphosphonate drug, Zolendronate, in combination with IL-2 and IL-15 cytokines to ART-treated SIV-infected macaques for in vivo expansion and enhanced IL-17/IL-22 function in Vd2T cells and evaluate the beneficial effect on IEBD, MT and inflammation. Finally, we propose to identify functional signatures of peripheral Vd2T and ILC3 subsets associated with plasma IEBD/MT markers, inflammation, and dysbiosis in PWH on ART. The goals of this multi-disciplinary study are to identify the mechanisms of dysregulation of IL-17/IL-22 pathway in Vd2T cells and ILC3, and their causal role in gut barrier damage, dysbiosis, and inflammation of HIV/SIV-infection during effective viral suppression with ART, and to (b) determine the contribution of Vd2 gdT cells to epithelial barrier functions and microbial homeostasis. Identification of the role played by key innate IL-17/IL-22 producing cells in the repair/loss of intestinal homeostasis is likely to have a critical impact on the management of enteropathy and inflammatory comorbidities in PWH.