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

Abstract

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. 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. 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. 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.