Utilizing the ex vivo rectal explant challenge model to evaluate HIV-1 Transmitted/Founder replication and inflammation within human gut mucosal tissue

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY Despite the remarkable viral sequence diversity observed within an individual during chronic HIV infection, the majority of new transmission events are established by a single HIV viral variant, aka the Transmitted Founder virus (T/F). Regardless of transmission route, replication of this T/F rapidly spreads from the mucosal site of transmission to distant tissue compartments within days of infection, including the gut mucosa, which contains a substantial proportion of the body’s lymphocytes. Viral replication within the gut mucosa contributes to loss of both gut barrier structural integrity and immunological homeostasis early in HIV infection. Ongoing translocation of microbial products across the damaged gut barrier into systemic circulation is thought to be a major contributor to the persistent inflammation described in persons living with HIV. This chronic inflammation a top research priority, as it has been associated with poor long-term health outcomes in persons living with HIV (PLHIV) highly relevant to the NIDDK, including the development of hyperglycemia and type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and chronic kidney disease. As T/F replication within the gut is responsible for the primary damage to the gut barrier in PLHIV, and, damage to the gut barrier is associated with poor health outcomes in PLHIV, we therefore hypothesize that differences in T/F replicative capacity within gut tissues is an undefined and under-appreciated factor which could contribute to an apparent sex-bias in comorbidity development between women and men living with HIV. That is, in addition to hypothesizing that T/Fs will display a broad range of replicative capacity within gut tissues (gvRC), we also hypothesize that gut tissues from women are a unique immune environment that will support higher levels of T/F replication, than tissues donated by men. To explore these concepts, in Aim 1, we will use the ex vivo rectal explant challenge model to define the gvRC of a unique collection of Subtype A, C, A/C T/F infectious molecular clones (n=24) in gut mucosal tissues donated by women and men (n=20/sex). In Aim 2, we will identify associations between gut resident immune cells in donated tissues and gvRC, and, critical clinical metrics such as increased rate of CD4 T cell decline, or elevated set-point viral-load, in the individuals from whom these T/F were isolated, while considering significant sex-based outcomes within Aim 1. Successful execution of these aims will lay the groundwork for future studies which seek to better understand the influence of sex on early viral and immunological events within the gut mucosa, with the goal of identifying novel targets for sex-appropriate biomedical interventions for PLHIV.