Intestinal Tissue-Resident Memory T Cells and HIV-1 Persistence During Antiretroviral Therapy

Tissue-resident memory T lymphocytes (TRM) are a specialized population of memory T cells that reside permanently within tissues and play a central role in local immune defense. In HIV-1 infection, the intestinal mucosa represents a major site of viral replication, immune dysfunction, and long-term viral persistence despite effective antiretroviral therapy (ART). Intestinal CD4+ T cells are highly susceptible to HIV-1 infection and undergo profound depletion early during infection, while incomplete immune restoration persists under ART.

Emerging evidence suggests that intestinal TRM CD4+ cells may be particularly susceptible to HIV-1 infection and may contribute to the maintenance of viral reservoirs because of their long lifespan and tissue retention properties. In parallel, TRM CD8+ cells may participate in local antiviral immune responses, although their functions may be impaired in the chronic inflammatory environment associated with HIV infection.

The objectives of this physiopathological study are to improve understanding of the mechanisms involved in defective restoration of intestinal TRM populations during suppressive ART and to evaluate the contribution of TRM CD4+ cells to HIV-1 persistence. Exploratory objectives include the phenotypic, transcriptomic, and functional characterization of intestinal TRM CD4+ and CD8+ cells; assessment of the susceptibility of intestinal TRM CD4+ cells to HIV-1 infection; evaluation of their role as viral reservoirs, including intact proviruses; and investigation of mechanisms regulating tissue retention and recirculation of ex-TRM cells in the intestinal mucosa.

This is a monocentric interventional physiopathological study with minimal risks and constraints (RIPH2). The study will enroll 20 people living with HIV-1 receiving suppressive ART and 10 HIV-seronegative controls matched for age and sex. Participants will be recruited among individuals undergoing routine colonoscopy, particularly for colorectal cancer screening indications. Study procedures consist of additional colonic mucosal biopsies collected during the clinically indicated colonoscopy and blood sampling performed on the day of the procedure.

I - Inclusion criteria

1 - Group 1: People Living With HIV-1

• Age ≥ 18 years
• Documented HIV-1 infection
• Continuous suppressive antiretroviral therapy initiated during chronic infection for at least 12 months
• Plasma HIV-1 RNA ≤ 50 copies/mL for at least 6 months under ART (one isolated blip ≤ 200 copies/mL allowed)
• Blood CD4+ T-cell count ≥ 350 cells/mm³
• Clinically indicated colonoscopy independent of the research protocol
• Affiliation with a social security system
• Written informed consent obtained before any study-specific procedure

2- Group 2: HIV-Seronegative Controls

• Age ≥ 18 years
• HIV-seronegative status
• Clinically indicated colonoscopy independent of the research protocol
• Affiliation with a social security system
• Written informed consent obtained before any study-specific procedure

II - Exclusion Criteria

• Group 1: People Living With HIV-1

• HIV-2 infection
• Inflammatory bowel disease (Crohn's disease or ulcerative colitis) or celiac disease
• Platelet count < 50 G/L or uncorrectable coagulation disorders contraindicating biopsies
• Decompensated cirrhosis
• History of lymphoma
• Participation in an HIV vaccine or immunotherapy study
• Pregnant or breastfeeding women
• Participation in another clinical study with an ongoing exclusion period
• Vulnerable individuals, including minors, individuals under guardianship, or persons deprived of liberty
• Group 2: HIV-Seronegative Controls

• HIV-1 or HIV-2 infection
• Refusal to undergo HIV serology testing
• Inflammatory bowel disease (Crohn's disease or ulcerative colitis) or celiac disease
• Platelet count < 50 G/L or uncorrectable coagulation disorders contraindicating biopsies
• Decompensated cirrhosis
• History of lymphoma
• Pregnant or breastfeeding women
• Participation in another clinical study with an ongoing exclusion period
• Vulnerable individuals, including minors, individuals under guardianship, or persons deprived of liberty