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

Abstract

Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)‐λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA‐C1C1 (P = 0.027), IFN‐λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA‐B (TapG:HLA‐B114D) (P = 0.007) and HLA‐DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN‐λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA‐C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non‐interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.

HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs

“…Of note, while on the genetic level we do not see a beneficial effect for KIR2DL3 and HLA-C1 in our German PWID cohort, we have previously reported that, on a phenotypic level, higher expression of KIR2DL3 is associated with spontaneous immune control of HCV and protection from infection (10). Collectively, the existing data from genetic association studies support the idea that the genetic correlates for "protection" against HCV infection are not universal and that the pathways to immune control involve multiple discrete factors (37). This also includes the genetic determinants of the CD8 + T cell response, that plays an important role in antiviral immunity against hepatitis C. In particular, presence of HLA-B*27 and HLA-B*57 was reproducibly associated with spontaneous immune control of HCV infection (38)(39)(40)(41).…”

Immune activation correlates with and predicts CXCR4 co-receptor tropism switch in HIV-1 infection

“…Exploratory univariate analysis of associations with co-receptor tropism was performed using the unpaired Students t-Test and Mann-Whitney Wilcoxon for continuous data, and χ 2 -test for categorical data. Subsequently, principal component analysis (PCA) was performed on immunological data, TB status, sex and age in order to account for multicollinearity of immunological marker data and distinguish between discrete immunological pathways 62 . Effect of principal components on X4-tropism was estimated using stepwise backward logistic regression with the first four principal components as independent variables and X4-tropism, defined at an FPR cut-off of ≤ 3.5%, as the dichotomous dependent variable (Table 3).…”

Decreased interferon‐γ production by NK cells from KIR haplotype B carriers in hepatitis C virus infection

“…Different clinical associations have been reported for KIR haplotype A, having being linked to protection against Hodgkin lymphoma and to a higher risk of conversion to acute myeloid leukaemia in myelodysplastic syndromes, while it was found increased in Mycobacterium tuberculosis ‐infected individuals . A recent study has shown that the haplotype B group included genes associated with chronic HCV infection and poor treatment response, but had a minor protective role against end stage manifestations including cirrhosis and hepatocellular carcinoma …”