Epigenetic modulation of intestinal epithelial dysfunction in HIV/SIV infection

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Texas Biomedical Research Institute $905,998 on September 1, 2026, to investigate epigenetic mechanisms driving intestinal epithelial dysfunction in people living with HIV receiving antiretroviral therapy, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847).

The research examines how aberrant DNA methylation and altered chromatin accessibility in colonic epithelium contribute to persistent gastrointestinal barrier disruption, microbial translocation, and systemic inflammation in treated HIV infection. The work uses chronically SIV-infected rhesus macaques as a model system to identify epigenetic alterations in genes regulating epithelial cell proliferation, inflammatory response, apoptosis, DNA damage response, and oxidative stress. Prior preliminary studies identified significant changes in DNA methylation of CpG islands and open chromatin accessibility in the colonic epithelium of SIV-infected macaques, and demonstrated that chronic phytocannabinoid treatment reduced these alterations and prevented dysbiosis in both ART-naïve and ART-experienced animals. The proposed studies will extend this work to characterize the degree to which DNA methylation changes regulate intestinal epithelial barrier function and assess effects on the size of the replication-competent latent gut HIV/SIV reservoir.

Performance occurs in San Antonio, Texas, with a period of performance from September 1, 2026, through July 31, 2030. Texas Biomedical Research Institute, doing business as Southwest Foundation for Biomedical Research, operates the Southwest National Primate Research Center and provides non-human primate models for infectious disease research.

Abstract

Gastrointestinal (GI) epithelial dysfunction persists in people living with HIV (PLWH) receiving suppressive anti- retroviral therapy (art), leading to epithelial barrier disruption, microbial translocation, and systemic inflammation-driven comorbidities. Although our understanding of pathogenesis has markedly improved, the molecular mechanisms remain poorly defined. Emerging evidence has shown that epigenetic mechanisms involving aberrant DNA methylation may significantly contribute to the pathogenesis of epithelial dysfunction in inflammatory bowel disease. Nevertheless, epigenetic mechanisms controlling immune and epithelial dysfunction in the GI tract of PLWH are understudied and a priority research area of the niddk nofo (PAS-24-163). Given that epigenetic marks are heritable and passed on to several generations of daughter cells during mitosis, this might explain a potential mechanism causing barrier disruption that could maintain persistent mucosal inflammation in PLWH on art. Our preliminary studies identified significant alterations in DNA methylation of CPG islands and open chromatin accessibility (single nuclei-atac-SEQ) in promoters of genes regulating epithelial cell proliferation, inflammatory response, apoptosis, dsdna damage response, and oxidative stress in the colonic epithelium of chronically SIV-infected rhesus macaques (RMS). While chronic phytocannabinoid treatment of art-naïve and experienced SIV-infected RMS reduced these epigenetic alterations and prevented dysbiosis, their effect on the size of the replication-competent latent GUT HIV/SIV reservoir remains unknown and unaddressed. Understanding the degree to which DNA methylation changes regulate the intestinal epithelial barrier is significant, as these studies are likely to reveal a novel but important role for epigenetic mechanisms in this process. In the proposed studies, we will for the first time investigate DNA methylation changes associated with intestinal epithelial dysfunction and its modulation by cannabinoids in HIV/SIV infection. Further, we will determine the effect of art in conjunction with cannabinoid treatments on immune activation/inflammation, and, more importantly, the latent HIV/SIV reservoir in the GI tract. Finally, we will investigate the receptor-mediated and molecular mechanisms by which cannabinoids regulate intestinal epithelial DNA methylation. The proposed research is highly innovative and applies state-of-the art immunological and molecular approaches to fill a significant GAP in our understanding of the role of DNA methylation in intestinal epithelial dysfunction. As cannabinoids have shown great promise for the treatment of digestive diseases, a better understanding of their molecular mechanism of action (epigenetic changes) and their effects on the HIV/SIV reservoir may lead to both a better understanding of the impact of cannabinoids in the context of abuse as well as leverage them for improving treatment outcomes (reducing comorbidities) in PLWH. Finally, the results will have important therapeutic implications for immune modulation in not only HIV but also other intestinal inflammatory diseases.