Intact proviruses are enriched in the colon and associated with PD-1+TIGIT- mucosal CD4+ T cells of people with HIV-1 on antiretroviral therapy

Background The persistence of intact replication -competent HIV -1 proviruses is responsible for the virological rebound off treatment. The gut could be a major reservoir of HIV -1 due to the high number of infected target cells. Methods We collected blood samples and intestinal biopsies (duodenum, ileum, colon) from 42 people with HIV -1 receiving effective antiretroviral therapy. We used the Intact Proviral DNA Assay to estimate the frequency of intact HIV -1 proviruses in the blood and in the intestinal mucosa of these individuals. We analyzed the genetic complexity of the HIV -1 reservoir by performing single -molecule next -generation sequencing of HIV -1 env DNA. The activation/ exhaustion profile of mucosal T lymphocytes was assessed by flow cytometry. Findings Intact proviruses are particularly enriched in the colon. Residual HIV -1 transcription in the gut is associated with persistent mucosal and systemic immune activation. The HIV -1 intestinal reservoir appears to be shaped by the proliferation of provirus-hosting cells. The genetic complexity of the viral reservoir in the colon is positively associated with TIGIT expression but negatively with PD -1, and inversely related to its intact content. The size of the intact reservoir in the colon is associated with PD-1+TIGIT- mucosal CD4+ T cells, particularly in CD27+ memory cells, whose proliferation and survival could contribute to the enrichment of the viral reservoir by intact proviruses. Interpretation Enrichment in intact proviruses makes the gut a key compartment for HIV -1 persistence on antiretroviral therapy. Funding This project was supported by grants from the ANRS-MIE (ANRS EP61 GALT), Sidaction, and the Institut Universitaire de France. Copyright (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).