Dataset Information

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4⁺ T-Cells by Decreasing Viral Release.

ABSTRACT: The mechanistic target of rapamycin (mTOR) positively regulates multiple steps of the HIV-1 replication cycle. We previously reported that a 12-weeks 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 CD4^lowHIV-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-transcription/translation steps of the HIV-1 replication cycle and may be used to accelerate viral reservoir decay in ART-treated PWH.

SUBMITTER: Fert A

PROVIDER: S-EPMC10925111 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4<sup>+</sup> T-Cells by Decreasing Viral Release.

Fert Augustine A Richard Jonathan J Marchand Laurence Raymond LR Planas Delphine D Routy Jean-Pierre JP Chomont Nicolas N Finzi Andrés A Ancuta Petronela P

bioRxiv : the preprint server for biology 20240219

The mechanistic target of rapamycin (mTOR) positively regulates multiple steps of the HIV-1 replication cycle. We previously reported that a 12-weeks 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<sup>+</sup> T-cells, together with systemic inflammation in nondiabetic people with HIV-1 (PWH). Herein, we investigated the antiviral mechanisms of met ...[more]

PMID: 38464135

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Project description:Human immunodeficiency virus type 1 (HIV-1) envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. In this study, we characterized a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i MAbs) that displayed characteristics of CD4i antibodies. Binding experiments demonstrated that the V2i MAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i MAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy showed recognition by V2i MAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the MAbs with CD4. We also characterized CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, bound to an Env trimer plus CD4. CG10 exhibited characteristics similar to those of the V2i antibodies, i.e., recognition of the open Env conformation, but showed direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection. IMPORTANCE The RV144 HIV-1 clinical vaccination trial showed modest protection against viral infection. Antibody responses to the V1V2 region of HIV-1 Env gp120 were correlated inversely with the risk of infection, and data from three other clinical vaccine trials suggested a similar signal. In addition, antibodies targeting V1V2 have been correlated with protections from simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infections in nonhuman primates. We structurally characterized V2i antibodies directed against V1V2 isolated from HIV-1 infected humans in complex with open Env trimers bound to the host receptor CD4. We also characterized a CD4i antibody that interacts with CD4 as well as the gp120 subunit of an open Env trimer. Our study suggests how V2i and CD4i antibodies were elicited during HIV-1 infection.

Dataset Information

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4⁺ T-Cells by Decreasing Viral Release.

Publications

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4<sup>+</sup> T-Cells by Decreasing Viral Release.

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Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release.

Publications

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4<sup>+</sup> T-Cells by Decreasing Viral Release.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4⁺ T-Cells by Decreasing Viral Release.