PMID- 33662832
OWN - NLM
STAT- MEDLINE
DCOM- 20211101
LR  - 20211204
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 65
DP  - 2021 Mar
TI  - LILAC pilot study: Effects of metformin on mTOR activation and HIV reservoir 
      persistence during antiretroviral therapy.
PG  - 103270
LID - S2352-3964(21)00063-3 [pii]
LID - 10.1016/j.ebiom.2021.103270 [doi]
LID - 103270
AB  - 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.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Planas, Delphine
AU  - Planas D
AD  - Departement de Microbiologie, Infectiologie et Immunologie, Faculte de Medecine, 
      Universite de Montreal, 900 rue Saint-Denis, Tour Viger R, room R09.416, 
      Montreal, Quebec H2 X 0A9, Canada; Centre de Recherche du CHUM du Centre 
      Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada. Electronic 
      address: delphine.planas@pasteur.fr.
FAU - Pagliuzza, Amelie
AU  - Pagliuzza A
AD  - Centre de Recherche du CHUM du Centre Hospitalier de l'Universite de Montreal, 
      Montreal, Quebec, Canada. Electronic address: 
      amelie.pagliuzza.chum@ssss.gouv.qc.ca.
FAU - Ponte, Rosalie
AU  - Ponte R
AD  - Infectious Diseases and Immunity in Global Health Program, Research Institute, 
      McGill University Health Centre, Montreal, Quebec, Canada; Chronic Viral Illness 
      Service, McGill University Health Centre, Montreal, Quebec, Canada. Electronic 
      address: ponte.rosalie@gmail.com.
FAU - Fert, Augustine
AU  - Fert A
AD  - Departement de Microbiologie, Infectiologie et Immunologie, Faculte de Medecine, 
      Universite de Montreal, 900 rue Saint-Denis, Tour Viger R, room R09.416, 
      Montreal, Quebec H2 X 0A9, Canada; Centre de Recherche du CHUM du Centre 
      Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada. Electronic 
      address: augustine.fert@umontreal.ca.
FAU - Marchand, Laurence Raymond
AU  - Marchand LR
AD  - Centre de Recherche du CHUM du Centre Hospitalier de l'Universite de Montreal, 
      Montreal, Quebec, Canada. Electronic address: 
      laurence.raymond-marchand.chum@ssss.gouv.qc.ca.
FAU - Massanella, Marta
AU  - Massanella M
AD  - Centre de Recherche du CHUM du Centre Hospitalier de l'Universite de Montreal, 
      Montreal, Quebec, Canada. Electronic address: mmassanella@irsicaixa.es.
FAU - Gosselin, Annie
AU  - Gosselin A
AD  - Centre de Recherche du CHUM du Centre Hospitalier de l'Universite de Montreal, 
      Montreal, Quebec, Canada. Electronic address: annie.gosselin.chum@gmail.com.
FAU - Mehraj, Vikram
AU  - Mehraj V
AD  - Infectious Diseases and Immunity in Global Health Program, Research Institute, 
      McGill University Health Centre, Montreal, Quebec, Canada; Chronic Viral Illness 
      Service, McGill University Health Centre, Montreal, Quebec, Canada. Electronic 
      address: vikram.mehraj@mail.mcgill.ca.
FAU - Dupuy, Franck P
AU  - Dupuy FP
AD  - Infectious Diseases and Immunity in Global Health Program, Research Institute, 
      McGill University Health Centre, Montreal, Quebec, Canada; Chronic Viral Illness 
      Service, McGill University Health Centre, Montreal, Quebec, Canada. Electronic 
      address: dura007@hotmail.fr.
FAU - Isnard, Stephane
AU  - Isnard S
AD  - Infectious Diseases and Immunity in Global Health Program, Research Institute, 
      McGill University Health Centre, Montreal, Quebec, Canada; Chronic Viral Illness 
      Service, McGill University Health Centre, Montreal, Quebec, Canada. Electronic 
      address: stephane.isnard@mail.mcgill.ca.
FAU - Goulet, Jean-Philippe
AU  - Goulet JP
AD  - Caprion, Montreal, Quebec, Canada. Electronic address: gouletjp@icloud.com.
FAU - Lesage, Sylvie
AU  - Lesage S
AD  - Departement de Microbiologie, Infectiologie et Immunologie, Faculte de Medecine, 
      Universite de Montreal, 900 rue Saint-Denis, Tour Viger R, room R09.416, 
      Montreal, Quebec H2 X 0A9, Canada; HMR Research Centre, Montreal, Quebec, Canada. 
      Electronic address: sylvie.lesage@umontreal.ca.
FAU - Cohen, Eric A
AU  - Cohen EA
AD  - Departement de Microbiologie, Infectiologie et Immunologie, Faculte de Medecine, 
      Universite de Montreal, 900 rue Saint-Denis, Tour Viger R, room R09.416, 
      Montreal, Quebec H2 X 0A9, Canada; Institut de Recherches Cliniques de Montreal, 
      Montreal, Quebec, Canada. Electronic address: Eric.Cohen@ircm.qc.ca.
FAU - Ghali, Mager Peter
AU  - Ghali MP
AD  - Division of Gastroenterology and Hepatology, McGill University, Montreal, Quebec, 
      Canada. Electronic address: ghali98@hotmail.com.
FAU - Angel, Jonathan B
AU  - Angel JB
AD  - Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of 
      Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address: 
      jangel@ohri.ca.
FAU - Chomont, Nicolas
AU  - Chomont N
AD  - Departement de Microbiologie, Infectiologie et Immunologie, Faculte de Medecine, 
      Universite de Montreal, 900 rue Saint-Denis, Tour Viger R, room R09.416, 
      Montreal, Quebec H2 X 0A9, Canada; Centre de Recherche du CHUM du Centre 
      Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada. Electronic 
      address: nicolas.chomont@umontreal.ca.
FAU - Routy, Jean-Pierre
AU  - Routy JP
AD  - Infectious Diseases and Immunity in Global Health Program, Research Institute, 
      McGill University Health Centre, Montreal, Quebec, Canada; Chronic Viral Illness 
      Service, McGill University Health Centre, Montreal, Quebec, Canada; Division of 
      Hematology, McGill University Health Centre, Montreal, Quebec, Canada. Electronic 
      address: jean-pierre.routy@mcgill.ca.
FAU - Ancuta, Petronela
AU  - Ancuta P
AD  - Departement de Microbiologie, Infectiologie et Immunologie, Faculte de Medecine, 
      Universite de Montreal, 900 rue Saint-Denis, Tour Viger R, room R09.416, 
      Montreal, Quebec H2 X 0A9, Canada; Centre de Recherche du CHUM du Centre 
      Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada. Electronic 
      address: petronela.ancuta@umontreal.ca.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
DEP - 20210301
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Anti-Retroviral Agents)
RN  - 0 (CCR6 protein, human)
RN  - 0 (Receptors, CCR6)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - EBioMedicine. 2021 Apr;66:103299. PMID: 33774325
MH  - Administration, Oral
MH  - Anti-Retroviral Agents/pharmacology/therapeutic use
MH  - CD4 Lymphocyte Count
MH  - CD4-Positive T-Lymphocytes/cytology/immunology/metabolism
MH  - CD8-Positive T-Lymphocytes/cytology/immunology/metabolism
MH  - Cell Survival/drug effects
MH  - Colon, Sigmoid/immunology/pathology
MH  - Disease Reservoirs/*virology
MH  - Drug Administration Schedule
MH  - HIV Infections/*drug therapy/virology
MH  - Humans
MH  - Metformin/pharmacology/*therapeutic use
MH  - Phosphorylation/drug effects
MH  - Pilot Projects
MH  - Receptors, CCR6/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Treatment Outcome
PMC - PMC7930590
OTO - NOTNLM
OT  - ART
OT  - HIV reservoirs
OT  - Metformin
OT  - Th17
OT  - mTOR
COIS- Declaration of Competing Interest EAC is a member of the Scientific Advisory 
      Board of Theratechnologies. JBA performed contract research and/or served on 
      Advisory Boards for Gilead Sciences Canada Inc., Merck Canada Inc., Abbvie Corp., 
      ViiV Healthcare, Bristol Myers Squibb, Janssen Inc., and Argos Pharmaceuticals. 
      NC received research funding from EMD Serono and served on Advisory Boards for 
      Gilead Sciences. JPR performed contract research and/or served on Advisory Boards 
      for Gilead Sciences Canada Inc., Merck Canada Inc., Abbvie Corp., ViiV 
      Healthcare, Bristol Myers Squibb, Janssen Inc., Argos Pharmaceuticals from 
      InnaVirVax, and Theravectys. PA's laboratory receives research funding from Glaxo 
      Smith Klein/NeoMed for projects not related to the present study. PA served as a 
      Consultant at Merck Canada Inc. relative to research projects different from the 
      present study. The other co-authors (DP, AP, RP, AF, LRM, MM, AG, VM, FPD, JPG, 
      SI, SL, and MPG) have no financial or non-financial competing interests to 
      disclose.
EDAT- 2021/03/05 06:00
MHDA- 2021/11/03 06:00
PMCR- 2021/03/01
CRDT- 2021/03/04 20:19
PHST- 2020/09/29 00:00 [received]
PHST- 2021/02/16 00:00 [revised]
PHST- 2021/02/19 00:00 [accepted]
PHST- 2021/03/05 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2021/03/04 20:19 [entrez]
PHST- 2021/03/01 00:00 [pmc-release]
AID - S2352-3964(21)00063-3 [pii]
AID - 103270 [pii]
AID - 10.1016/j.ebiom.2021.103270 [doi]
PST - ppublish
SO  - EBioMedicine. 2021 Mar;65:103270. doi: 10.1016/j.ebiom.2021.103270. Epub 2021 Mar 
      1.