The miRNomics of antiretroviral therapy-induced obesity

Abstract

Human immunodeficiency virus (HIV) is a retrovirus that incorporates its genetic material into the host's chromosome. The resulting diseases and related conditions constitute a global health problem as there are no treatments to eliminate HIV from an infected individual. However, the potent, complex, and active antiretroviral therapy (ART) strategies have been able to successfully inhibit HIV replication in patients. Unfortunately, obesity following ART is frequent among HIV-infected patients. The mechanism underlying ART-induced obesity is characterized based on expression of traditional markers such as genes and proteins. However, little is known about, yet another key component of molecular biology known as microRNAs (miRNAs). Micro-RNAs are ~ 22 base-long non-coding nucleotides capable of regulating more than 60% of all human protein-coding genes. The interest in miRNA molecules is increasing and their roles in HIV and obesity are beginning to be apparent. In this review, we provide an overview of HIV and its associated diseases, ART-induced obesity, and discuss the roles and plausible benefits of miRNAs in regulating obesity genes in HIV-infected patients. Understanding the roles of miRNAs in ART-induced obesity will aid in tracking the disease progression and designing beneficial therapeutic approaches.

Keywords: ART; HAART; HIV; MiRNA; Obesity.

Fig. 1

ARVs may induce obesity via modulating mitochondrial function (Rodriguez et al. 2024), inflammation (Mave et al. 2016), or activation of immune system (Pedro et al. 2018)

Fig. 2

Key regions in miRNA structure. the 5'-P anchor, which is crucial for miRNA stability and its incorporation into the RNA-induced silencing complex (RISC) (Noland et al. 2011); the seed region, typically covering nucleotides 2–7 from the 5' end essential for recognizing and binding complementary sequences on the target mRNA(Kilikevicius et al. ; McGeary et al. 2022); the central region which provides additional stability in the miRNA-mRNA interaction; the 3' supplementary region, enhancing binding specificity and stability by complementing sequences downstream on the mRNA (McGeary et al. 2022); and the 3'-OH tail region, aiding in the overall stability of the miRNA within the RISC. The presence of these organized areas allows the miRNA to efficiently direct the RISC to its target mRNA. This may result in either the breakdown of the mRNA or the prevention of its translation, hence controlling gene expression in different biological processes (Iwakawa and Tomari 2022)

Fig. 3

Predicted outcomes of ARV-induced obesity. ART, cART, HAART, and PI’s (Saquinavir-SQV and Lopinavir/Ritonavir-LPV/RPV) are known to induce miRNAs. These drugs may inhibit (Red box) or induce expression of miRNAs (Green box). ART is known to induce miR-214-5p, miR-15b-5p, and miR-532-3p (Bresciani et al. ; Squillace et al. 2014); SQV and LPV/RPV induce miR-222-5p, miR-483-5p and miR-2185p, respectively (Bresciani et al. ; Polus et al. 2017); cART induces miR-125a-5p and miR-30c while lowering expression of miR-122-5p and miR-194-5p (Chai et al. ; Kinoo et al. ; Squillace et al. 2014); and HAART repress expression of miR-27a (Bresciani et al. 2019). The model is based on the miRNA effects on the target molecules that are either published or predicted (KLF5) (Palioura et al. 2022) by us. The drug induced changes to miRNA > target expressions may result in beige fat accumulation (Shen et al. 2022), fat accumulation in torso (Bresciani et al. 2022), enhance preadipocyte proliferation (Xu et al. 2018) and triglyceride synthesis (Benavides-Aguilar et al. ; Bresciani et al. ; Karbiener et al. 2011), impaired insulin sensitivity (Li et al. 2020a), insulin resistance (Gallo et al. 2018), and hypercholesterolemia (Kinoo et al. 2023); all of which promote different aspects of obesity in HIV patients under ARV