Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source

Abstract

The role of cytotoxic T lymphocyte responses, restricted by human leukocyte antigen (HLA) class I alleles, is recognized as highly significant in the successful clearance of hepatitis C virus (HCV). The frequency of class I alleles in females inoculated with HCV genotype 1b from a single source was examined for an association with outcome. Class I typing was performed using polymerase chain reaction sequence-specific primers in 227 female subjects: 141 had chronic infection and 86 had viral clearance. Statistical analysis included 2 testing and multiple logistic regression analysis. A*03, B*27, and Cw*01 occurred more frequently in those with viral clearance (39.5%, 14%, and 9.3%, respectively) compared with those with chronic infection (19.1%, 2.1%, and 1.4%, respectively; P < .005). B*08 occurred more often in those with chronic infection compared with viral clearance (39.7% vs. H epatitis C virus (HCV) is a hepatotropic virus with a high rate of chronic infection. It is known that progression to cirrhosis and hepatocellular carcinoma may take up to 20 years in individuals who are chronically infected and thus represents a leading cause of hepatocellular morbidity and mortality. [1][2][3][4] To date, viral factors (e.g., genotype) and host factors (e.g., age of acquisition, male sex, and alcohol consumption) are known to alter both the natural history of the disease and treatment outcomes. 2,4-6 As yet, no in vivo models of infection are available in HCV infection, therefore the pathogenic mechanism of disease remains unclear. 19.8%; P ‫؍‬ .002). In combination with previously reported class II allele associations, overIn HCV infection, recognition and elimination of infected cells by cytotoxic T lymphocytes (CTLs) require the presentation of specific HCV antigens on the membrane of hepatocytes in the context of HLA-A, -B and -C antigens. In acute HCV infection, animal models suggest that viral clearance appears to be dependent on an intrahepatic CTL response directed against multiple HCV antigens restricted by several class I molecules. 7 Human studies on peripheral blood similarly report that viral clearance is associated with a strong initial HCV-specific

Associations between the human MHC and sustained virologic response in the treatment of chronic hepatitis C virus infection

“…We observed 10,7,8,8 and 6 alleles at the DRB1, DQA1, DQB1, DPA1 and DPB1 loci, respectively, within the class II region X5%. Table 2 presents the raceadjusted Mantel-Haenszel w 2 test results for the four alleles with a race-adjusted P-value less than or equal to 0.05; results for all alleles evaluated by Mantel-Haenszel w 2 tests are listed in Supplementary Tables 1 and 2 (available at the Genes and Immunity web site).…”

“…9 The A*02-B*27-Cw*01 haplotype was found in strong LD with the DRB1*0101-DQB1*0501 haplotype, which was associated with HCV clearance in an Irish population, as were the B*27 and Cw*01 alleles alone. 10 This could indicate that one or more loci in LD with A*02 are influencing immune response to hepatitis C infection. In our sample, two subjects (1 AA and 1 CA) carried both A*02 and B*58, four subjects (2 AA and 2 CA) carried both A*02 and DPB1*1701, five subjects (all AAs) carried both B*58 and DPB1*1701, and no subjects carried all three alleles, therefore, we did not investigate haplotype associations in this cohort.…”

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

“…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. In terms of HLA‐class I, HLA‐B*08 has been linked to viral persistence in the Irish HCV and an US cohort, but could not be replicated in an East German population 33, 34, 35. HLA‐DQB1*0301 was found to be protective in largely Caucasian cohorts in France, the UK and Italy, but only in black populations in the United States, showing that geographical location, and hence the infecting HCV virion may be a determinant of response rather than ethnicity alone 18, 36, 37, 38.…”

HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

“…Clearance of hepatitis C virus, for example, has been associated with HLA-A*03 and B*27 alleles while CTLs expressing different but closely related HLA molecules have shown significant functional differences when targeting identical HIV epitopes (16)(17)(18). Recent studies have highlighted HLA class I associations with both EBV-positive HL and NPC.…”