Circulating MicroRNAs as a Tool for Diagnosis of Liver Disease Progression in People Living with HIV-1

Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding specific cell mRNA targets, preventing their translation. miRNAs are implicated in the regulation of important physiological and pathological pathways. Liver disease, including injury, fibrosis, metabolism dysregulation, and tumor development disrupts liver-associated miRNAs. In addition to their effect in the originating tissue, miRNAs can also circulate in body fluids. miRNA release is an important form of intercellular communication that plays a role in the physiological and pathological processes underlying multiple diseases. Circulating plasma levels of miRNAs have been identified as potential disease biomarkers. One of the main challenges clinics face is the lack of available noninvasive biomarkers for diagnosing and predicting the different stages of liver disease (e.g., nonalcoholic fatty liver disease and nonalcoholic steatohepatitis), particularly among individuals infected with human immunodeficiency virus type 1 (HIV-1). Liver disease is a leading cause of death unrelated to acquired immunodeficiency syndrome (AIDS) among people living with HIV-1 (PLWH). Here, we review and discuss the utility of circulating miRNAs as biomarkers for early diagnosis, prognosis, and assessment of liver disease in PLWH. Remarkably, the identification of dysregulated miRNA expression may also identify targets for new therapeutics.

Keywords: HIV-1; biomarker; diagnosis; liver injury; miRNAs; prognosis.

Figure 1

Molecular mechanism of the repressor activity of microRNAs. (A) miRNAs bind target mRNAs and repress their expression. (B) The stoichiometry of target mRNAs and miRNAs governs mRNA expression. In the presence of a disease state, the expression of a miRNA may be upregulated or downregulated and, consequently, the miRNA and target stoichiometry may change and the corresponding mRNA expression be altered. Although not shown in this figure, the opposite situation can also occur; disease may alter the expression of an mRNA and modify the amount of free miRNA, which may have an effect elsewhere.

Figure 2

Most relevant mechanisms of liver injury in people living with HIV-1. Mechanisms by which different disease entities may cause hepatic injury and fibrosis include oxidative stress, mitochondrial injury, lipotoxicity, immune-mediated injury, cytotoxicity, toxic metabolite accumulation, gut microbial translocation, systemic inflammation, senescence, and nodular regenerative hyperplasia. HIV-1 may use any number of these mechanisms to exert an effect on the liver [19].

Figure 3

Signatures of deregulated circulating microRNAs in different infected populations. Venn diagram showing circulating plasma miRNAs with significant (fold change > 2 and adjusted p < 0.05) differences between healthy samples (n = 21) and different infected populations: HIV-1-monoinfected (n = 53), HCV-monoinfected (n = 17), and HIV-1/HCV-coinfected (n = 50). Data were obtained from two studies [65,88]. miRNA profile data were generated by small RNA sequencing of individual plasma samples. Downregulated circulating miRNAs are shown in red and upregulated circulating miRNAs in black.