Hepatitis C Virus and the Host: A Mutual Endurance Leaving Indelible Scars in the Host's Immunity

Abstract

Hepatitis C virus (HCV) has spread worldwide, and it is responsible for potentially severe chronic liver disease and primary liver cancer. Chronic infection remains for life if not spontaneously eliminated and viral persistence profoundly impairs the efficiency of the host's immunity. Attempts have been made to develop an effective vaccine, but efficacy trials have met with failure. The availability of highly efficacious direct-acting antivirals (DAA) has created hope for the progressive elimination of chronic HCV infections; however, this approach requires a monumental global effort. HCV elicits a prompt innate immune response in the host, characterized by a robust production of interferon-α (IFN-α), although interference in IFN-α signaling by HCV proteins may curb this effect. The late appearance of largely ineffective neutralizing antibodies and the progressive exhaustion of T cells, particularly CD8 T cells, result in the inability to eradicate the virus in most infected patients. Moreover, an HCV cure resulting from DAA treatment does not completely restore the normal immunologic homeostasis. Here, we discuss the main immunological features of immune responses to HCV and the epigenetic scars that chronic viral persistence leaves behind.

Keywords: HCV; adaptive immunity; innate immunity.

Figure 1

Schematic overview depicting the impact of chronic HCV infection and direct-acting antivirals (DAA) on the immune response. (A) During chronic infection, there is a heightened production of type I and III interferons and enhanced expression of IFN-stimulated genes (ISGs). NK cells show a functional impairment marked by increased expression of inhibitory molecule PD-1, reduced FcγRIII expression, and decreased ADCC activity and IFN-γ and TNF-α secretion, despite increased degranulation. T cell exhaustion occurs during chronic infection with increased expression of inhibitory molecules (PD-1, CTLA-4, TIGIT, TIM-3) and epigenetic imprints. B cells exhibit chronic activation, polyclonal expansion, and elevated markers of atypical memory cells. Cryoglobulinemia and rheumatoid factors may be present. (B) DAA treatment reduces ISG expression while maintaining a notable presence of soluble inflammatory mediators. NK cell status reverts to physiological homeostasis after viral eradication. However, complete functional restoration remains uncertain, leaving residual defects such as suboptimal antibody-dependent cell-mediated cytotoxicity (ADCC). T cell recovery post-DAA cure is also only partial, leaving long-lasting epigenetic scars. The B cell phenotype and physiological levels of T-bet⁺ B cells are restored, yet the oligoclonality of B cells may persist even after HCV eradication, potentially in a quiescent state. DAA treatment for cryoglobulinemia results in remission in only about half of the patients. Upward arrows means increase and downward arrows decrease. Created with Biorender.com.