Acute Hepatitis C Infection is Associated with an Increase in Circulating microRNA-122
Ramy El-Diwany1, Kimberly Page2, Stuart Ray1, Andrea Cox1, David L. Thomas1, Ashwin Balagopal1
1Center for Viral Hepatitis Research, Johns Hopkins School of Medicine, Baltimore, MD; 2Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
Background: Circulating microRNAs (miRNAs) are increasingly recognized as early and stable biomarkers of disease. miR122 is an abundant hepatocyte-derived miRNA that is required for hepatitis C virus (HCV) replication, and increased circulating cell-free miR-122 has been associated with chronic HCV in cross-sectional studies. We measured cell-free miRNAs, including miR-122, before and immediately after incident HCV infection. Methods: Samples were obtained from the Baltimore Before and After Acute Study of Hepatitis (BBAASH), a longitudinal study of injection drug users (IDU)that collects monthly blood specimens. In this prospective study, most infections are asymptomatic, avoiding bias toward severe cytolysis. Twentytwo participants who acquired acute HCV infection and either spontaneously cleared infection (“clearers”; n=11)or developed persistent infection (“persisters”; n=11) were identified who had plasma available at four time points: i) pre-infection; ii) first viremia; iii) last viremia in clearers; and iv) post-viremia in clearers. Samples from persisters were time-matched withthose from clearers for all time points. RNA was extracted from plasma and the relative abundance of approximately 800 microRNAs was determined using a quantitative PCR array. Individual Taqman® RT/qPCR assays were performed to validate findings from the array, and miR-122a was quantified in relation to the spiked-in control microRNA from Arabidopsis thaliana, ath-miR-159a. Findings were confirmed in 29 participants in the You Find Out (UFO) cohort, a separate longitudinal study of IDU who acquired incident HCV infection. Results: BBAASH participants΄ ages ranged from 20-31 years, 13 (59%) were female, and 20 (91%) were white. mir-122 levels rose a median (IQR) of 5.3-fold (0.8-39.2) upon first viremia compared to pre-infection levels (p=0.02). miR-122 varied directly with transaminases at all time points; however, miR155 and miR-146a, miRNAs that have been previously associated with hepatocyte damage, were not elevated upon infection (p=0.98 and p=0.92, respectively). miR-122 levels stayed elevated compared to pre-infection in persisters at the latest time points (p=0.001), while miR-122 decreased in clearers to pre-infection levels (p=0.57). miR-122 levels showed similar increases upon acute HCV infection in the UFO cohort (p=0.02). Conclusions: Circulating miR-122 increases soon after HCV infection and normalizes in persons who spontaneously clear infection. Plasma miR-122 may be an early and unique marker of acute HCV infection.
Stuart Ray - Advisory Committees or Review Panels: Abbott Laboratories, Boerhinger Ingelheim
David L. Thomas - Grant/Research Support: Merck, Gilead
The following people have nothing to disclose: Ramy El-Diwany, Kimberly Page, Andrea Cox, Ashwin Balagopal