CD8+ T Cells Mediate Colon Epithelial Cell Death in an Organoid Model of HIV Pathogenesis

There are 37.9 million people worldwide living with HIV [1] and although advances in antiretroviral treatment (ART) have significantly extended life expectancy, the burden of HIV-associated comorbidities remains high [2,3,4,5]. Gut epithelial barrier disruption is a hallmark of HIV infection and even after decades of ART, markers of intestinal barrier disruption remain persistently elevated in some individuals [6,7]. Gut barrier disruption can result in the translocation of luminal bacteria and bacterial products, leading to systemic inflammation [8,9]. The specific mechanisms of this HIV-associated gut epithelial barrier disruption remain incompletely understood, but it is believed to be a critical driver of the increased prevalence of inflammation-associated comorbidities observed in those with ART-treated HIV [10]. We demonstrated that intestinal epithelial cells from HIV-infected individuals undergo increased apoptosis in comparison to those from HIV-uninfected individuals. Employing an ex vivo 3D mini-colon organoid model cocultured with autologous colon mucosal lymphocytes, we showed that this epithelial cell death can also be seen ex vivo in HIV-infected lymphocyte-organoid co-cultures derived from HIV-uninfected individuals. Moreover, colon epithelial cell death is dependent upon tissue resident CD8+ T cells, excluding HIV-specific CD8+ T cells. We also show that CD8+ T cell derived TNF and IFN are dispensable for mediating the epithelial cell death. Since the molecular characteristics of colon tissue resident CD8+ T cells in the context of chronic viral infection are largely unknown, our current work seeks to elucidate the inherent metabolic programming of these colon tissue resident CD8+ T cells. The metabolic profile of colon tissue resident CD8+ T cells may contribute to the observed epithelial cell death in the context of HIV pathogenesis. These findings may help identify novel methods to better treat those living with HIV.