Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release

Abstract

Plasma microRNAs (miRNAs) change in abundance in response to disease and have been associated with liver fibrosis severity in chronic hepatitis C virus (HCV) infection. However, the early dynamics of miRNA release during acute HCV infection are poorly understood. In addition, circulating miRNA signatures have been difficult to reproduce among separate populations. We studied plasma miRNA abundance during acute HCV infection to identify an miRNA signature of early infection. We measured 754 plasma miRNAs by quantitative PCR array in a discovery cohort of 22 individuals before and during acute HCV infection and after spontaneous resolution (n ‫؍‬ 11) or persistence (n ‫؍‬ 11) to identify a plasma miRNA signature. The discovery cohort derived from the Baltimore Before and After Acute Study of Hepatitis. During acute HCV infection, increases in miR-122 (P < 0.01) and miR-885-5p (P corrected < 0.05) and a decrease in miR-494 (P corrected < 0.05) were observed at the earliest time points after virus detection. Changes in miR-122 and miR-885-5p were sustained in persistent (P < 0.001) but not resolved HCV infection. The circulating miRNA signature of acute HCV infection was confirmed in a separate validation cohort that was derived from the San Francisco-based You Find Out (UFO) Study (n ‫؍‬ 28). As further confirmation, cellular changes of signature miRNAs were examined in a tissue culture model of HCV in hepatoma cells: HCV infection induced extracellular release of miR-122 and miR-885-5p despite unperturbed intracellular levels. In contrast, miR-494 accumulated intracellularly (P < 0.05). Collectively, these data are inconsistent with necrolytic release of hepatocyte miRNAs into the plasma during acute HCV infection of humans. IMPORTANCEMicroRNAs are small noncoding RNA molecules that emerging research shows can transmit regulatory signals between cells in health and disease. HCV infects 2% of humans worldwide, and chronic HCV infection is a major cause of severe liver disease. We profiled plasma miRNAs in injection drug users before, during, and (in the people with resolution) after HCV infection. We discovered miRNA signatures of acute and persistent viremia and confirmed these findings two ways: (i) in a separate cohort of people with newly acquired HCV infection and (ii) in an HCV cell culture system. Our results demonstrate that acute HCV infection induces early changes in the abundance of specific plasma miRNAs that may affect the host response to HCV infection. H epatitis C virus (HCV) is a single-stranded positive-sense hepatotropic RNA virus that infects over 170 million people worldwide. Acute HCV infection progresses to chronic infection in ϳ75% of cases (1-3). Little is understood about early hostpathogen interactions due to a lack of representative animal models and the difficulty in studying acute HCV, which is largely asymptomatic.MicroRNAs (miRNAs) are 18-to 25-nucleotide noncoding RNA molecules with widespread gene network regulatory capacity. miRNAs are readily detectable in cell-free compo...

An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection

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Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

“…39,40 An association between miRNAs and non-lytic herpesvirus and hepatitis C virus infection has been reported. 41,42 Recent reports support the role of miRNAs in enterovirus pathogenesis. 43 An improved understanding of the impact of viral persistence on the host cell and the virus could provide new insights into the enteroviral pathogenesis of T1D.…”

Systematic Identification and Bioinformatic Analysis of MicroRNAs in Response to Infections of Coxsackievirus A16 and Enterovirus 71

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