Metformin facilitates viral reservoir reactivation and their recognition by anti-HIV-1 envelope antibodies
Augustine Fert,
Jonathan Richard,
Laurence Raymond Marchand,
Delphine Planas,
Jean-Pierre Routy,
Nicolas Chomont,
Andrés Finzi,
Petronela Ancuta
Affiliations
Augustine Fert
Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
Jonathan Richard
Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
Laurence Raymond Marchand
Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada
Delphine Planas
Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
Jean-Pierre Routy
Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada; Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada; Division of Hematology, McGill University Health Centre, Montreal, QC, Canada
Nicolas Chomont
Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
Andrés Finzi
Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
Petronela Ancuta
Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada; Corresponding author
Summary: The mechanistic target of rapamycin (mTOR) positively regulates multiple steps of the HIV-1 replication cycle. We previously reported that a 12-week supplementation of antiretroviral therapy (ART) with metformin, an indirect mTOR inhibitor used in type-2 diabetes treatment, reduced mTOR activation and HIV transcription in colon-infiltrating CD4+ T cells, together with systemic inflammation in nondiabetic people with HIV-1 (PWH). Herein, we investigated the antiviral mechanisms of metformin. In a viral outgrowth assay performed with CD4+ T cells from ART-treated PWH, and upon infection in vitro with replication-competent and VSV-G-pseudotyped HIV-1, metformin decreased virion release, but increased the frequency of productively infected CD4lowHIV-p24+ T cells. These observations coincided with increased BST2/tetherin (HIV release inhibitor) and Bcl-2 (pro-survival factor) expression, and improved recognition of productively infected T cells by HIV-1 envelope antibodies. Thus, metformin exerts pleiotropic effects on post-integration steps of the HIV-1 replication cycle and may be used to accelerate viral reservoir decay in ART-treated PWH.
