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Large-scale screening of circulating microRNAs in individuals with HIV-1 mono-infections reveals specific liver damage signatures

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1)-induced inflammation and/or long-term antiretroviral drug toxicity may contribute to the evolution of liver disease. We investigated circulating plasma microRNAs (miRNAs) as potential biomarkers of liver injury in patients mono-infected with HIV-1. We performed large-scale deep sequencing analyses of small RNA level on plasma samples from patients with HIV-1 mono-infection that had elevated or normal levels of alanine aminotransferase (ALT) or focal nodular hyperplasia (FNH). Hepatitis C virus (HCV) mono-infected patients were also studied. Compared to healthy donors, patients with HIV-1 or HCV mono-infections showed significantly altered (fold change >2, adjusted p<0.05) level of 25 and 70 miRNAs, respectively. Of the 25 altered miRNAs found in patients with HIV-1, 19 were also found in patients mono-infected with HCV. Moreover, 13 of the 14 most up-regulated miRNAs (range: 9.3-3.4-fold increase) in patients with HCV mono-infections were also up-regulated in patients with HIV-1 mono-infections. Importantly, most of these miRNAs significantly and positively correlated with ALT and aspartate aminotransferase (AST) levels, and liver fibrosis stage (p<0.05). MiR-122-3p and miR-193b-5p were highly up-regulated HIV-1 mono-infected patients with elevated ALT or FNH, but not in HIV-1 patients with normal levels of ALT. These results reveal that HIV-1 infections impacted liver-related miRNA levels in the absence of an HCV co-infection, which highlights the potential of miRNAs as biomarkers for the progression of liver injury in HIV-1 infected patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141522 | GEO | 2019/12/06

REPOSITORIES: GEO

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Project description:Hepatitis C virus (HCV) remains a significant public health threat as new 1.75 million HCV infections emerged worldwide. The majority of these infections become persistently infected, while around 30 % spontaneously eliminate the virus. Clinical factors for viral clarification are related to HCV interaction with host immune system, but little is known about the consequences after HCV spontaneous resolution. These individuals are difficult to recruit and study as acute infection is usually asymptomatic, and they will not be identified unless it progress to chronic infection. The study of peripheral blood mononuclear cells (PBMCs) of these patients is crucial, as PBMCs are one of the main HCV extrahepatic reservoirs, and its transcriptional profile provide us information of innate and adaptive immune response against HCV infection. Our research shows novel insight on molecular consequences of spontaneous resolution after an acute HCV infection. 96 Individuals with different HCV exposure status were recruited: spontaneous resolved, chronic infected and healthy controls; and the microRNA profile of their PBMCs were analyzed. Our results indicate similar disruption of miRNA expression on HCV chronic patients and those who spontaneously clarified the infection, compared to control patients. The disrupted miRNAs formed a signature of 21 miRNAs that mainly regulate lipid metabolism. This is the first report showing miRNA profile similarities between chronic HCV patients and spontaneous resolved individuals. Thus, our results suggest that HCV infection promotes molecular alterations in PBMCs that will last longer after HCV spontaneous eradication. This evidences open up new prospects in the management of individuals who spontaneously clarified infection, as they should be monitored and followed to dismiss future HCV-related complications, such us liver diseases complications. The identified miRNA signature could be used as biomarker to monitor HCV fingerprint on HCV-exposed patients.

Project description:End stage liver disease due to Hepatitis C Virus (HCV) infection is a major health concern worldwide. Liver fibrosis following chronic HCV infection plays a pivotal role in loss of liver function and end stage liver disease. However the dynamics and molecular events that lead to fibrosis in HCV infection are poorly defined. Therefore, we determined the influence of HCV infection in altering the miRNA expression levels which can modulate immune responses to HCV leading to fibrosis. Analysis of the miRNA expression profiles of HCV infected liver biopsies revealed that 45 miRNAs were differentially expressed in the HCV infected liver when compared to normal livers. In silico target prediction of these differentially expressed miRNAs indicated that their targets include chemokine/cytokine signaling, cell cycle genes and extracellular matrix protein gene expression. Gene expression profiling using whole genome microarray demonstrated that 1320 genes were differentially expressed in chronic HCV liver when compared to normal. These genes could be functionally grouped into those involved in cell cycle regulation, cytokines and chemokines expression, cell adhesion, intracellular signaling and enzymes. Further pathway analysis using GeneGo software identified cell adhesion, cytoskeleton remodeling, cytokine signaling and metabolic pathways as the major pathways activated in chronic HCV. Combinatorial target prediction analysis of miRNA expression along with gene expression analysis indicated that differentially expressed microRNAs in HCV significantly impact transforming growth factor beta (TGF-?) signaling pathway, cell adhesion (integrin expression), chemokine signaling, Notch signaling and cell-cycle( Cyclin D,K) regulation. Overall these results demonstrate that chronic HCV infection induces specific miRNA signatures that will modulate genes involved in the cytoskeletal remodeling and cytokine signaling that can promote the development of fibrosis following HCV infection. Liver biopsies from chronic HCV patients and control liver biopsies from normal subjects (donor liver prior to transplantation) were used to analyze the miRNA and gene expression profile. Patients with HBV and/or HIV were excluded from the study. This Series represents the mRNA gene expression profiling data only.

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Large-scale screening of circulating microRNAs in individuals with HIV-1 mono-infections reveals specific liver damage signatures

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