Date Published: September 17, 2018
Publisher: Public Library of Science
Author(s): Brad R. Rosenberg, Marion Depla, Catherine A. Freije, Denis Gaucher, Sabrina Mazouz, Maude Boisvert, Nathalie Bédard, Julie Bruneau, Charles M. Rice, Naglaa H. Shoukry, Lynn Dustin.
Most individuals exposed to hepatitis C virus (HCV) become persistently infected while a minority spontaneously eliminate the virus. Although early immune events influence infection outcome, the cellular composition, molecular effectors, and timeframe of the host response active shortly after viral exposure remain incompletely understood. Employing specimens collected from people who inject drugs (PWID) with high risk of HCV exposure, we utilized RNA-Seq and blood transcriptome module (BTM) analysis to characterize immune function in peripheral blood mononuclear cells (PBMC) before, during, and after acute HCV infection resulting in spontaneous resolution. Our results provide a detailed description of innate immune programs active in peripheral blood during acute HCV infection, which include prominent type I interferon and inflammatory signatures. Innate immune gene expression rapidly returns to pre-infection levels upon viral clearance. Comparative analyses using peripheral blood gene expression profiles from other viral and vaccine studies demonstrate similarities in the immune responses to acute HCV and flaviviruses. Of note, both acute dengue virus (DENV) infection and acute HCV infection elicit similar innate antiviral signatures. However, while transient in DENV infection, this signature was sustained for many weeks in the response to HCV. These results represent the first longitudinal transcriptomic characterization of human immune function in PBMC during acute HCV infection and identify several dynamically regulated features of the complex response to natural HCV exposure.
Despite the recent breakthrough of highly effective direct acting antiviral therapies, hepatitis C virus (HCV) remains a significant public health threat. New infections, especially among people who inject drugs (PWID), are likely to increase in the absence of a prophylactic vaccine . Effective vaccine development is hampered by our limited understanding of how protective immunity is established in the acute stages of natural infections. Acute HCV infection has two dichotomous outcomes, spontaneous resolution (~25% of infections) or chronic infection (~75% of infections) . Immune functions following viral exposure remain incompletely understood due in part to the limited availability of paired pre-infection and longitudinal acute infection research samples from recently exposed, largely asymptomatic individuals.
Here we present a detailed transcriptomic characterization of early events in the human immune response to acute HCV infection in individuals that progress to spontaneous resolution. We detected wide-ranging changes in PBMC gene expression patterns, including those consistent with pronounced innate antiviral programs and inflammatory mediators. The patterns observed in the PBMC response to acute HCV shared many features with effective immune responses to YFV and acute DENV infection. To our knowledge, this study represents the first longitudinal transcriptomic investigation of the PBMC response to acute HCV in humans.