Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection in patients with spontaneous viral clearance

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.Author summary: Hepatitis C virus (HCV) is a leading cause of liver disease, with an estimated 71 million people infected worldwide. Following exposure, a subset of individuals spontaneously clears the virus while a majority progress to chronic infection. The immune functions active during the initial, acute infection by HCV are not well understood, due in part to difficulties associated with studying the early stages of this disease in humans. Most individuals acutely infected with HCV are asymptomatic and do not initially seek medical care, which presents challenges in conducting prospective longitudinal studies. Here, by employing specimens from a rare research cohort of individuals sampled before infection, during infection, and after spontaneous viral clearance, we use RNA-Seq to characterize the early immune processes active in acute HCV. Our analysis identified a robust innate antiviral gene signature that corresponds with HCV viremia. In addition, comparisons to other immune transcriptomics datasets demonstrated that the immune response to acute HCV shares many features with responses to flaviviruses. These results offer a detailed longitudinal description of immune function active during the spontaneous resolution of acute HCV infection and provide insight into the early events that may contribute to viral clearance.