HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection

Khakoo, Salim I.; Thio, Chloe L.; Martin, Maureen P.; Brooks, Collin; Gao, Xiaojiang; Astemborski, Jacquie; Cheng, Jie; Goedert, James J.; Vlahov, David; Hilgartner, Margaret W.; Cox, S.T.; Little, A.‐M.; Alexander, Graeme; Cramp, Matthew; O’Brien, Stephen J.; Rosenberg, William; Thomas, David L.; Carrington, Mary

doi:10.1126/science.1097670

Cited by 1,076 publications

(1,045 citation statements)

References 22 publications

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“…The recent association of HLA and NK cell receptor genes with HCV clearance saw genetic effects at low infectious doses (only in those who did not receive blood products). 54 A similar infectious dose response for CMV with the murine NK cell receptor Ly49 H has also been observed. 55,56 Together with the observation that essentially all significant associations were seen in lowdose IVDUs who happen to be African American in this study, our results support further evaluation of variants at IL10, IL19, and IL20 in HCV clearance.…”

Section: Discussionmentioning

confidence: 59%

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

et al. 2005

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Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (7300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P ¼ 0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P ¼ 0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.

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Section: Discussionmentioning

confidence: 59%

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

et al. 2005

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“…Heterogeneity at a population level has continued to contribute to substantial variation seen between studies in HCV resolution. For example for KIR in the UK population, KIR2DL3:HLA‐C1 is protective 8, but this is not found in the cohort of Irish women infected from a single source 20. In a Swiss cohort, the rs8099917 IFN‐λ3/4 minor allele failed to show any association with treatment in patients infected with HCV G2/3, but this was not the case when later repeated in a cohort of over 1000 Australians, also of Caucasian ethnicity 6, 32.…”

Section: Discussionmentioning

confidence: 99%

“…The killer cell immunoglobulin (KIR) and human leukocyte antigen (HLA) combinations are also important for HCV outcomes in spontaneously resolving infection, IFN‐treatment‐associated resolution and in European‐exposed seronegative individuals 8, 14. 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.…”

Section: Introductionmentioning

confidence: 85%

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

et al. 2015

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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.

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“…This situation is extremely unlikely without the impact of a form of natural selection called balancing selection, which maintains genetic variation of specific loci in the population 55. Indeed, all human populations studied to date have a representation of KIR A and B haplotypes51, 56 and the prevailing hypothesis is that the A haplotypes are good for fighting infection57, 58 whereas B haplotypes are more beneficial for reproduction 17, 59…”

Section: Kir Geneticsmentioning

confidence: 99%

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

et al. 2016

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SummaryKiller‐cell immunoglobulin‐like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease.

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HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection

Cited by 1,076 publications

References 22 publications

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

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

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

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