PROJECT SUMMARY
Gut dysfunction, dysbiosis, and residual inflammation are major factors contributing to the high prevalence of
comorbidities such as metabolic, cardiovascular, kidney, and liver diseases in people living with HIV under
antiretroviral therapy (ART). However, the immune mechanisms underlying the process of gut dysfunction and
persistent inflammation in the setting of long-term viral suppression with ART remain poorly understood. We
have recently reported in the nonhuman primate model of HIV with ART that following initial resolution of
circulating leaky gut biomarkers during early ART, dysregulation of IL-17/IL-22 functions of intestinal Gamma
delta (¿d) T cells are correlated with resurgence of intestinal epithelial barrier damage (IEBD) and systemic
inflammation during long-term ART. Further, intestinal Vd2T cell frequencies significantly correlated with the loss
of specific gut microbial species during long-term ART. Based on this, we propose to test the hypothesis that
specific dysregulation of the IL-17/IL-22 pathway in ¿dT cells, particularly the Vd2 subset, contributes to
breakdown of the gut epithelial barrier, resulting in microbial translocation (MT) and systemic inflammation during
chronic treated HIV infection. Here, we propose to assess the role of Vd2 ¿dT cells in the repair and maintenance
of gut homeostasis through a direct in vivo intervention. We will evaluate the effect of in vivo Vd2T-stimulation
and expansion on IEBD, MT, and inflammation in long-term ART suppressed SIV-infection via treatment with
the aminobisphosphonate drug, Zoledronate (ZOL) in combination with IL-2 and IL-15 cytokines. Second, we
propose to test the hypothesis that modulation of gut microbiome during chronic SIV+ART with microbial
supplementation combined with in vivo Vd2T cell stimulation will have a synergistic effect on improving gut barrier
functions. We will administer fecal microbial transplant (FMT) supplemented with anti-inflammatory bacterial
species, with/without ZOL treatment to assess normalization of systemic inflammatory markers and gut immune
functions in FMT-only vs. FMT with immunomodulation. Finally, we will determine the mechanisms by which ¿dT
cells and microbiome modulate intestinal epithelial homeostasis during long-term treated SIV infection. We will
longitudinally assess the transcriptional and functional signatures of intestinal IL-17/IL-22 producing cells and
evaluate epithelial barrier functions in precisely timed gut biopsies and in vitro coculture assays to identify novel
cellular/molecular mechanisms involved. By exploring the beneficial effects of combined immune/microbiome
modulation on epithelial barrier-protective function and systemic inflammation, this study will have the critical
impact of opening new avenues for the continued development of combinatorial approaches to target
enteropathy and chronic inflammation in people living with HIV.
