Exploring the Role of Caspase-1-Mediated-Pyroptosis in Promoting Chronic Inflammation in HIV Patients

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The depletion of CD4 T cells and the development of chronic inflammation are signature processes in HIV pathogenesis that propel progression to AIDS. Our recent ex vivo studies have revealed how most lymphoid CD4 T cells die by caspase-1-mediated-pyroptosis, an intensely inflammatory form of programmed cell death, providing an unexpected association between these two disease-promoting processes. The objective of this proposal is to further extend our findings into in vivo analyses of HIV infected subjects, in particularly cART-treated virologic controllers who display chronic inflammation despite complete or near-complete suppression of HIV replication. The mechanisms contributing to such persistent inflammation remains a key question in the field. We hypothesize that caspase-1-mediated pyroptosis in mucosal and peripheral lymphoid organs plays a major role in promoting such inflammation. Moreover, pyroptosis initiated by HIV may trigger pyroptosis in nearby CD4 T cells by releasing intracellular 5'-ATP. Such response could result in persistent rounds of pyroptosis leading to chronic inflammation even when viral replication is effectively reduced. We will collaborate with Dr. Peter Hunt (see letter of support and biosketch), co-investigator with the SCOPE Cohort at UCSF, who will provide access to a group of 1500 well-characterized contemporary HIV-infected patients of diverse demographic and clinical status. Importantly, a repository of rectal, ileal, lymph node biopsies and blood samples from candidates already exists and ready for analysis. We will use multiple experimental tools including IHC, frozen tissue analyses (Cryostat) and flow cytometry to explore the extent of pyroptosis in these tissues, and its association to established immune activation markers. We anticipate that completion of these investigations, including data analysis and conclusions, will take approximately 1 year. Statistical consultation will be provided by the UCSF Biostatistical Consulting Unit. Understanding the mechanisms for pyroptosis and inflammation could lead to improved approaches for curing HIV infection and/or reducing inflammation-associated disease.