# The intestinal interferon system and specialized enterocytes as putative drivers of HIV latency

## TL;DR

This review explores how specialized gut cells and interferon activity may help maintain HIV latency in the gut, offering new insights for HIV cure strategies.

## Contribution

The paper proposes a novel hypothesis linking interferon activity in specialized enterocytes to the persistence of the HIV reservoir in the gut.

## Key findings

- The gastrointestinal tract contains a significant portion of the HIV reservoir.
- Interferon signaling in specialized enterocytes may create a microenvironment that supports HIV latency.
- Dysregulated interferon signaling in the gut could contribute to HIV persistence and reactivation.

## Abstract

The barrier to HIV cure is the HIV reservoir, which is composed of latently infected CD4+ T cells and myeloid cells that carry stably integrated and replication-competent provirus. The gastrointestinal tract (GIT) contains a substantial part of the HIV reservoir and its immunophysiology could be especially conducive for HIV persistence and reactivation. However, the exact cellular microenvironment and molecular mechanisms that govern the renewal of provirus-harboring cells and proviral reactivation in the GIT remain unclear. In this review, we outline the evidence supporting an overarching hypothesis that interferon activity driven by specialized enterocytes creates a microenvironment that fosters proliferation of latently infected CD4+ T cells and sporadic HIV reactivation from these cells. First, we describe unique immunologic features of the gastrointestinal associated lymphoid tissue (GALT), specifically highlighting IFN activity in specialized enterocytes and potential interactions between these cells and neighboring HIV susceptible cells. Then, we will describe dysregulation of IFN signaling in HIV infection and how IFN dysregulation in the GALT may contribute to the persistence and reactivation of the latent HIV reservoir. Finally, we will speculate on the clinical implications of this hypothesis for HIV cure strategies and outline the next steps.