Innate and adaptive genetic pathways in HCV infection

Abstract

Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes.

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

“…In these studies, the combination of KIR2DL3 and its HLA‐C group 1 ligands (HLA‐C1) was protective in all groups tested in our UK population. These findings have been confirmed in sub‐groups in other populations, but it is clear that there is population diversity in how the KIR gene family contributes to the resolution of HCV infection 15. The influence of KIR diversity remains important in the era of triple therapy, until directly acting anti‐viral therapies become cost effective 16, 17.…”

A significant effect of the killer cell immunoglobulin‐like receptor ligand human leucocyte antigen‐C on fibrosis progression in chronic C hepatitis with or without liver transplantation

“…NK cells are involved in the anti‐HCV immune response, and among the multiple NK cell receptors, distinct KIR have been associated with a better viral clearance . The regulation of NK cells through the expression of activating and inhibitory KIR is dependent of the expression of HLA ligands at the cell surface of the target cells.…”

“…A strong association of both innate and adaptive immunity polymorphisms with HCV clearance and with the progression of HCV‐related liver diseases has been proposed . Notably, polymorphisms of interferon (IFN)‐λ, natural killer (NK) cells and specific CD4 and CD8 T cells response to HCV are critical.…”

“…The balance between activating and inhibitory signals has been shown to be critical for the modulation of NK cells effector functions. Among these receptors, the killer cell immunoglobulin–like receptors (KIR) encoded by a cluster of genes on chromosome 19 are of particular interest , as several of them have been previously associated to HCV infection outcome . This includes the inhibitory KIR receptors KIR2DL2, KIR2DL3 , KIR2DL1 and KIR3DL1 , which recognize human leucocyte antigen (HLA)‐C alleles with an asparagines at position 80 (HLA‐C group 1), HLA‐C alleles with a lysine at position 80 (HLA‐C group 2) and HLA‐B alleles carrying the Bw4 epitope respectively.…”

“…19 and 6 respectively), individuals may lack the corresponding HLA ligand for a given KIR receptor. This has a significant influence on the strength of activating or inhibiting signals that NK cells will receive, and this explains why in most of the studies that have found an association of KIR with HCV outcome, an association with the presence or absence of one or several HLA class I ligands was also observed . In liver transplantation situation, the lack of a corresponding ligand is even more expected because KIR and HLA are coming from two genetically unrelated individuals, i.e.…”