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Writer's pictureDavid Ojcius

Metformin facilitates viral reservoir reactivation and their recognition by anti-HIV-1 envelope antibodies

Highlights

#Metformin increases the frequency of productively #HIV-infected T cells

• Metformin acts on HIV-1 replication cycle at post-entry and post-integration levels

• Metformin increases BST2 and Bcl-2 expression in productively HIV-infected T cells

• Metformin increases viral reservoir recognition by anti-HIV-Env Abs



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.


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