1 Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada. firstname.lastname@example.org.
2 Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada. Jordan.Feld@uhn.ca.
3 Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada. Jordan.Feld@uhn.ca.
4 Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada. email@example.com.
5 Departments of Laboratory Medicine & Pathobiology and Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada. firstname.lastname@example.org.
Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.