Genes of the major histocompatibility complex class II influence the outcome of hepatitis C virus infection

doi:10.1053/gast.1997.v113.pm9352872

Gastroenterology

Volume 113, Issue 5, November 1997, Pages 1675-1681

https://doi.org/10.1053/gast.1997.v113.pm9352872 Get rights and content

Abstract

BACKGROUND & AIMS: The host's immune response may influence the course of hepatitis C virus (HCV) infection. The aim of this study was to investigate the distribution of HLA class II alleles in white subjects who spontaneously recovered from HCV infection compared with that in patients with persistent infection.

METHODS: HLA-DRB1 and -DQB1 typing were performed in 103 consecutive patients with persistent HCV infection (HCV antibody positive, HCV RNA positive) and in 25 subjects with transient HCV infection (HCV antibody positive, persistently negative HCV RNA).

RESULTS: No significant differences between subjects with transient or persistent infection were observed for age, sex, source of infection, or HCV serotype. The frequency of DQB1*0301 and DRB1*1101 alleles was higher in patients with transient infection than in those with persistent infection (84% vs. 30.8%, 40% vs. 9.8%; P < 0.01 and P < 0.02, respectively [Bonferroni correction]). DRB1 and DQB1 alleles did not influence viral load as an independent factor. Mean Knodell's scores were lower in patients with DQB1*0301 allele (6.12 +/- 0.4) than in those negative for DQB1*0301 (7.37 +/- 0.3; P < 0.05).

CONCLUSIONS: Our results suggest that host- rather than virus-related factors are probably involved in the spontaneous clearance of HCV.

(Gastroenterology 1997 Nov;113(5):1675-81)

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This is a multi-site international consortium including multiple studies from Europe and United States in which HCV infection outcomes were ascertained. They include ALIVE (AIDS Link to the Intravenous Experience),18 BBAASH (Baltimore Before and After Acute Study of Hepatitis),19 BAHSTION (Boston Acute Hepatitis C Virus Study: Transmission, Immunity and Outcomes Network),13 Cramp and colleagues’ study,20 HGDS (Hemophilia Growth and Development Study),21 Mangia and colleagues’ study,22 MHCS (Multicenter Hemophilia Cohort Study) and MHCS-II,23 REVELL (Correlates of Resolved Versus Low-Level Viremic Hepatitis C Infection in Blood Donors) study,24 the Swan Project,25 the Toulouse, France cohort,15 WIHS (Women’s Interagency HIV Study),26 the United Kingdom Drug Use cohort,27 and the Urban Health Study (UHS)28,29 as described in detail in elsewhere.5,6,17 These studies were selected because they had well-established hepatitis C virus (HCV) outcomes, as previously described,5,6,17 available DNA, and IRB approval for genetic testing.
Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p value_Meta = 1.24 × 10⁻¹⁴) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p value_Meta = 8.23 × 10⁻¹¹) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r² < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1^∗03:01, and HLA-DRB1^∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC₅₀ nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10⁻³⁸). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.
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Introduction and aim. Hepatitis C virus (HCV) infection is a global medical problem. HLA -DRB1 alleles have an important role in immune response against HCV. The aim of this study is to clarify the contribution of HLA -DRB1 alleles in HCV susceptibility in a multicentre family-based study.
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In addition, Thio et al. (1999) showed a significant association between haplotype cluster of DQA1*0501-DQB1*0301DQB1*1102 and viral persistence. Moreover, it is identified that the alleles DRB1*1101 and DQB1*0301 are associated with spontaneous elimination of HCV (Alric et al., 1997; Minton et al., 1998; Thursz et al., 1999). In contrast, Zavaglia et al. (1996) did not show any association between HLA phenotypes and clearance of HBV or HCV virus.
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