Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

Abstract

Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy.

Genetic Variants in KIR/HLA-C Genes Are Associated With the Susceptibility to HCV Infection in a High-Risk Chinese Population

“…The activating receptor KIR2DS4 recognizes unique, selective HLA-C molecules and six HLA-C allotypes (three carrying the C1 epitope and three carrying the C2 epitope) can reliably bind KIR2DS4 (45). The activating KIR2DS4/ KIR2DS1 or the inhibitory KIR2DL1, which exerts stronger effect than activating ones, has to interact with HLA-C presenting on healthy or diseased cells to affect NK cell activity (19). As mentioned above, the risk alleles of rs35440472 and rs1130838 could affect the expression of three KIR genes as well as HLA-C, respectively.…”

“…NK cells would be elicited and exert their antiviral effector functions to participate in immune responses (16,17). However, aberrant activation of NK cells resulting in excessive or low immune responses may lead to persistent infection (18,19). Not surprisingly, the exertion of NK cell function is directly impacted by the genetic variations of KIRs and HLA-I molecules (12,20).…”

HLA Alleles and KIR Genes in Romanian Patients with Chronic Hepatitis C

“…HLA-B *57-mediated antiviral immunity confers protection for HCV and HIV infections. This suggests a common shared mechanism of a successful immune response against persistent viruses [36][37][38]. Neumann-Haefelin et al [39] note that the protection associated with the HLA-B*27 allele has been linked to an epitope identified in genotype 1 infections but was not identified in genotype 3 infections in German patients.…”

Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection

“…In chronic HCV infection, IFN-α has been identified as an activator of intrahepatic NK cells [ 60 ]. Consequently, the function of NK cells is altered during chronic HCV infection, with amplified cytotoxicity and decreased levels of cytokine production, including IFN-γ ( Figure 1 ) [ 61 , 62 , 63 ]. Thus, a functional dichotomy is created.…”