A crucial role for novel miR-12137-3p in supporting weight gain in treatment naïve HIV-infected patients on antiretroviral therapies.

BACKGROUND

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. MiRNAs are implicated in diverse biological processes. However, their specific role in antiretroviral (ARV) therapy-induced obesity in individuals with Human Immunodeficiency Virus (HIV) represents an area requiring further investigation.

METHODS

Patient data and blood samples were collected according to the inclusion and exclusion criteria. Next generation sequencing (NGS) was performed to determine the changes in circulatory miRNA profiles in response to an integrase strand transfer inhibitor (INSTI; Biktarvy)-and protease inhibitor (PI; Symtuza)-based ARV treatment in promoting obesity in treatment naïve HIV-infected patients. Cloning, dual luciferase reporter assay, in vitro studies employing differentiated adipocyte-Chub-S7 cells in the presence of miRNA specific mimics and/or inhibitors, and PCR arrays were performed for the mechanistic studies.

RESULTS

Our study yielded the following results: (i) both the drugs (Biktarvy and Symtuza) were equally good at managing HIV infection; (ii) patients on both these ARV treatment seem to show a weight gain trend as early as 24 weeks post treatment; (iii) expression of a novel miRNA, miR-12137-3p, was elevated in the plasma of HIV-infected patients experiencing weight gain while on ARV treatment (INSTI or PI-based ARV); (iv) PPARγ-2 and WNT3A were determined to be the direct targets of miR-12137-3p; and (v) inhibiting miR-12137-3p-associated cell signaling in differentiated adipocyte-Chub-S7 cells with miR-12137-3p inhibitor significantly lowered lipid droplet accumulations within the cells. We also employed PCR arrays to further understand the role of miR-12137-3p in weight gain/obesity.

CONCLUSION

The study reports for the first time a role for novel miRNA, miR-12137-3p, in ARV-associated weight gain/obesity. Further understanding the biology of miR-12137-3p may offer novel therapeutic approaches to treating weight gain in general.

CLINICAL TRIAL NUMBER: ClinicalTrials.gov ID - NCT05463783. Date of registration: 03/14/2023; https://clinicaltrials.gov/study/NCT05463783 .