Understanding the Mechanism of HIV Associated with Diabetic Complications in Low- and Middle-Income Country

PROJECT SUMMARY Our proposed project is designed to investigate the immunopathological basis of NK cell-mediated pancreatic insufficiency which may lead to the future occurrence of diabetes mellitus (DM) among people living with HIV (PLWH). Furthermore, we plan to explore HIV/antiretroviral therapy-induced endoplasmic reticulum (ER) stress as a contributory pathophysiological phenomenon which would render pancreatic tissue more susceptible to immune-mediated destruction in this population, with attempts to mitigate this through low-cost, ER stress- inhibiting medication. Our comprehensive analysis of the altered immunophenotype among PLWH has revealed several subsets of activated, pro-inflammatory NK cells dominating the circulation. We have also successfully demonstrated direct effects of these altered NK cells among PLWH in contributing to the ongoing risk of other non-communicable diseases (NCDs) like atherosclerotic cardiovascular disease at a very young age. Based on our previous research findings and existing literature, we have gathered sufficient evidence to back our proposed studies. Our epidemiological findings have collectively predicted an increased risk of DM in an expanding HIV population dominated by young adults in Sri Lanka, a lower-middle income country (LMIC) in South Asia, which relies heavily on an active workforce for sustenance of its fragile economy. We strongly believe that our proposed work and its main outcomes may broaden our understanding of the NK cell-mediated immunopathogenesis of such NCDs and socioeconomically acceptable therapeutic/preventive strategies which could be implemented in these critical populations in the future. We also believe that our exploratory study would create a significant impact and ignite further research in this field of study. By conducting this project in an LMIC setting like Sri Lanka, we hope to foster a network of research collaborations between two diverse settings, with plans to strengthen the research infrastructure related to HIV and its comorbidities in Sri Lanka. Through our proposed scientific techniques such as high-dimensional flow cytometry, novel immunohistochemical techniques, transcriptomics and epigenomics, we hope to carryout exchange of knowledge and expertise and between our study settings and help build necessary infrastructure in Sri Lanka in an effort to lay the groundwork for future collaborations on HIV related research in this setting.