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Restoration of HCV-Specific Immune Responses With Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection


Restoration of HCV-Specific Immune Responses With Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection

Julia L Casey et al. Cells.


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.

Keywords: DAAs; Hepatitis C Virus; IFN; direct acting antivirals; exhausted T cells; immune exhaustion; immune restoration; interferon.

Conflict of interest statement

J.l.C. and S.A.M. declare no conflict of interest. J.J.F. has received honoraria for scientific consulting from AbbVie, Gilead, and Merck, and his institution has received research support from AbbVie, Gilead, Janssen, Merck.


Figure 1
Figure 1
HCV-specific Immune Restoration following IFN and DAA therapy administered during the acute and chronic phase of HCV infection. HCV is characterized by an acute phase of infection in which the immune response is unable to control HCV replication, leading to chronicity in the majority of patients. Following IFN-α therapy administered during acute HCV infection: CD8+ T cell populations expressed low levels of exhaustion marker, PD-1 and increased levels of memory marker CD127, anti-apoptotic marker Bcl-2 and IFN-γ production. Following IFN-α therapy administered during chronic HCV infection: CD8+ T cell populations expressed high level PD-1 and low level of CD127 and IFN-γ production. Immune restoration following DAA therapy administered during acute HCV infection has not been documented in the literature. Following DAA therapy administered during chronic HCV infection: Literature demonstrates varying results. Decreased PD-1 and increased CD127 has been reported, while no change in PD-1 expression post-treatment has also been reported.

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