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.
