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      LILAC pilot study: Effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

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          Abstract

          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.

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          Most cited references80

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          mTOR Signaling in Growth, Metabolism, and Disease.

          The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.
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            mTOR at the nexus of nutrition, growth, ageing and disease

            The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway’s central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.
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              The mechanisms of action of metformin

              Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4342-z) contains a slideset of the figures for download, which is available to authorised users.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                01 March 2021
                March 2021
                01 March 2021
                : 65
                : 103270
                Affiliations
                [a ]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
                [b ]Centre de Recherché du CHUM du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
                [c ]Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, Quebec, Canada
                [d ]Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
                [e ]Caprion, Montréal, Québec, Canada
                [f ]HMR Research Centre, Montreal, Quebec, Canada
                [g ]Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada
                [h ]Division of Gastroenterology and Hepatology, McGill University, Montreal, Quebec, Canada
                [i ]Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
                [j ]Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
                [k ]Division of Hematology, McGill University Health Centre, Montreal, Quebec, Canada
                Author notes
                [* ]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. jean-pierre.routy@ 123456mcgill.ca petronela.ancuta@ 123456umontreal.ca
                [1]

                Present address Institut Pasteur, Paris, France.

                [2]

                Equal contribution.

                Article
                S2352-3964(21)00063-3 103270
                10.1016/j.ebiom.2021.103270
                7930590
                33662832
                3a2e9a0f-abe5-4de6-9870-da09ef914cfa
                © 2021 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Research paper

                metformin,art,hiv reservoirs,th17,mtor
                metformin, art, hiv reservoirs, th17, mtor

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