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

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.

Keywords: ART; HIV reservoirs; Metformin; Th17; mTOR.