LILAC pilot study: Effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy
Delphine Planas,
Amélie Pagliuzza,
Rosalie Ponte,
Augustine Fert,
Laurence Raymond Marchand,
Marta Massanella,
Annie Gosselin,
Vikram Mehraj,
Franck P Dupuy,
Stéphane Isnard,
Jean-Philippe Goulet,
Sylvie Lesage,
Eric A. Cohen,
Mager Peter Ghali,
Jonathan B. Angel,
Nicolas Chomont,
Jean-Pierre Routy,
Petronela Ancuta
Affiliations
Delphine Planas
Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2 X 0A9, Canada; Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
Amélie Pagliuzza
Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
Rosalie Ponte
Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, Quebec, Canada; Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
Augustine Fert
Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2 X 0A9, Canada; Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
Laurence Raymond Marchand
Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
Marta Massanella
Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
Annie Gosselin
Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
Vikram Mehraj
Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, Quebec, Canada; Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
Franck P Dupuy
Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, Quebec, Canada; Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
Stéphane Isnard
Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, Quebec, Canada; Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
Jean-Philippe Goulet
Caprion, Montréal, Québec, Canada
Sylvie Lesage
Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2 X 0A9, Canada; HMR Research Centre, Montreal, Quebec, Canada
Eric A. Cohen
Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2 X 0A9, Canada; Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada
Mager Peter Ghali
Division of Gastroenterology and Hepatology, McGill University, Montreal, Quebec, Canada
Jonathan B. Angel
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
Nicolas Chomont
Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2 X 0A9, Canada; Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
Jean-Pierre Routy
Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, Quebec, Canada; Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada; Division of Hematology, McGill University Health Centre, Montreal, Quebec, Canada; Corresponding authors at: Petronela Ancuta, PhD, CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2X 0A9, Canada; and Jean-Pierre Routy, MD, FRCPC; Research Institute of McGill University Health Centre: Glen site; 1001 Boulevard Décarie, EM 3-3232, Montreal, QC, H4A 3J1, Canada.
Petronela Ancuta
Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2 X 0A9, Canada; Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Corresponding authors at: Petronela Ancuta, PhD, CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, Quebec H2X 0A9, Canada; and Jean-Pierre Routy, MD, FRCPC; Research Institute of McGill University Health Centre: Glen site; 1001 Boulevard Décarie, EM 3-3232, Montreal, QC, H4A 3J1, Canada.
Background: Chronic inflammation and residual HIV transcription persist in people living with HIV (PLWH) receiving antiretroviral therapy (ART), thus increasing the risk of developing non-AIDS co-morbidities. The mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism and HIV transcription, and therefore represents an interesting novel therapeutic target. Methods: The LILAC pilot clinical trial, performed on non-diabetic ART-treated PLWH with CD4+/CD8+ T-cell ratios <0.8, evaluated the effects of metformin (12 weeks oral administration; 500-850 mg twice daily), an indirect mTOR inhibitor, on the dynamics of immunological/virological markers and changes in mTOR activation/phosphorylation in blood collected at Baseline, Week 12, and 12 weeks after metformin discontinuation (Week 24) and sigmoid colon biopsies (SCB) collected at Baseline and Week 12. Findings: CD4+ T-cell counts, CD4+/CD8+ T-cell ratios, plasma markers of inflammation/gut damage, as well as levels of cell-associated integrated HIV-DNA and HIV-RNA, and transcriptionally-inducible HIV reservoirs, underwent minor variations in the blood in response to metformin. The highest levels of mTOR activation/phosphorylation were observed in SCB at Baseline. Consistently, metformin significantly decreased CD4+ T-cell infiltration in the colon, as well as mTOR activation/phosphorylation, especially in CD4+ T-cells expressing the Th17 marker CCR6. Also, metformin decreased the HIV-RNA/HIV-DNA ratios, a surrogate marker of viral transcription, in colon-infiltrating CD4+ T-cells of 8/13 participants. Interpretation: These results are consistent with the fact that metformin preferentially acts on the intestine and that mTOR activation/phosphorylation selectively occurs in colon-infiltrating CCR6+CD4+ T-cells. Future randomized clinical trials should evaluate the benefits of long-term metformin supplementation of ART.
