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
Camille Vellas, Manon Nayrac, Nived Collercandy, Mary Réquena, Nicolas Jeanne, Justine Latour, Chloé Dimeglio, Michelle Cazabat, Karl Barange, Laurent Alric, Nicolas Carrère, Guillaume Martin‐Blondel, Jacques Izopet, Pierre Delobel
Abstract
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.