The major histocompatibility loci that encode the HLA class I and II molecules, which recognize and bind T-cell epitopes in viral proteins, represent among the most highly polymorphic genes in the human population. In this cohort study of genetically diverse patients with chronic HCV infection, we observed that the A*02, B*58 and DPB1*1701 HLA alleles were independently associated with SVR even after adjustment for other predictors of response such as race, gender, baseline viral load, severity of liver fibrosis and dosage of medication taken. While these alleles do not explain all of the observed racial differences in response to peginterferon-ribavirin therapy, they might be contributing factors that work in conjunction with other factors to affect differences in response.
We note that A*02 is positively associated with SVR (P = 0.008, ) in both CA and AA samples and is more frequent among CA patients (46% carrier frequency) than among AA patients (30%). Conceivably, this difference in A*02 frequency between the two ethnic groups might account, in part, for the increased SVR rate among Caucasian patients. The other highly significant association in this data set with SVR is for B*58 (P = 0.002, ). This allele is found more frequently among AA patients (14% carrier frequency) than among CA patients (1%). However, as B*58 is much less frequent among AA patients than A*02 is among CA patients, this allele may have less effect on the relative SVR rates of the two populations than does A*02.
In the regression model containing all alleles with other predictors of response (), we observed different levels of significance for those alleles in the AA and CA subgroups compared to each other and compared to the combined sample. These subgroup evaluations should be interpreted with caution as both subgroups contain fewer than 200 subjects (AA n = 179 and CA n = 194), some allele frequencies were very low in certain subgroups (), and, particularly for the AA subgroup, the number of subjects achieving SVR is small; thereby contributing to the wider confidence intervals and lack of statistical significance observed in the subgroup analyses. Nevertheless, the RR estimates () within the subgroups and in the combined sample were in the same direction for all alleles and, for A*02, of a similar magnitude. For B*58 and DPB1*1701, the RR estimates in the AA subgroup were larger than those in the CA subgroup indicating a possible heterogeneity of effect between our AA and CA study samples for these alleles or others in strong LD (linkage disequilibrium) with B*58 or DPB1*1701.
None of these three alleles have previously been reported in association with response to peginterferon plus ribavirin therapy for HCV infection. The A*02 antigen was reported in association with lower alanine transaminase levels in chronically HCV-infected Japanese subjects.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 A*02 allele has been reported in association with other infectious diseases and/or complications. In particular, in Japanese subjects infected with human T-cell lymphotropic virus type I (HTLV-I), the A*02 allele was associated with protection from HTLV-I-associated myelopathy, and in healthy carriers of HTLV-I, the A*02 allele was associated with lower viral load.11
The A*02-Cw16 haplotype was associated with high viral load in HIV-1, clade C-infected Zambians.12
Finally, a study of C282Y homozygous hemochromatosis subjects demonstrated a significant association between the A*02 allele and a lower CD8+ T-lymphocyte count.13
This association was not observed in healthy controls carrying the A*02 allele, indicating that the lower count may be related to a locus in LD with the A*02 allele. We identified one published report14
of an association between the B*5802 allele and higher viral load in HIV-1 subtype C-infected Zambians, although the B*5801-Cw*03 haplotype was associated with lower viral load. Furthermore, an association between the B*58 allele and higher T-cell response in vertically-HIV-infected AA children (predominately females) has been reported.15
Differences in the immunogenetic background of HCV-infected individuals might, in part, account for the observed variation in viral-specific immunity and courses of disease.16
In this regard, binding of HCV peptides to HLA molecules is a critical step for the initiation of an antigen-specific immune response. Previous work from Virahep-C has indicated that baseline HCV-specific immunity is associated with SVR;17
patients with higher levels of CD4 + T-cell responses are more likely to develop SVR than patients with lower pretreatment levels. Moreover, the frequency of circulating effector cytotoxic T-cell lymphocytes before treatment was also shown to predict SVR.18
It is of considerable interest that the A*02 allele, the most common restricting allele for known HCV epitopes (http://www.hcv.lanl.gov
), was strongly associated with SVR in the current study. Thus, one might speculate that a patient carrying the HLA A*02 allele would have a considerably greater likelihood of having T cells that recognize HCV peptides displayed on infected hepatocytes compared to patients not carrying this allele. This relatively augmented immune background might lead to HCV that is more susceptible to the antiviral pressure induced by therapy. The relative rarity of HLA B*58 limits its clinical utility as a predictor of response; notably, no known HCV epitopes restricted by this allele have been reported (http://www.hcv.lanl.gov
). On the other hand, it is conceivable that HLA genotyping for A*02 might provide additional prognostic information for patients with chronic HCV undergoing antiviral therapy.
Our study involved a select group of patients undergoing a standardized treatment protocol.5
Participants had to meet specific selection criteria: all had mild fibrosis, were interferon-treatment naïve and were infected with genotype-1 HCV. Future studies examining a broader patient population are warranted. Additionally, our study employed medium resolution typing of the MHC region; studies of higher resolution typing might further inform the relationship between MHC alleles and SVR in the treatment of hepatitis C. Studies are also needed to understand the function of HLA molecules and how they present HCV antigens. Moreover, the elimination of HCV during therapy is a dynamic process that occurs over the course of time. It is possible that alleles capable of presenting a broad range of HCV antigens are needed at certain time points during the elimination of the virus, while other alleles, more specific with respect to the HCV antigens that they present, are needed at other time points. Future studies should identify whether alleles with different HCV antigen-presenting characteristics are needed at different time points during the course of therapy. In conclusion, we observed that certain MHC gene variants were associated with SVR to peginterferon-ribavirin therapy. These MHC associations by themselves, however, are insufficient to account for the observed differences in AA and CA response rates even though there are large differences between AA and CA allele frequencies for the associated variants. Thus, our data suggest that one or more additional genetic factors contribute to the racial difference in response. Confirmation of these results in other AA and CA populations, as well as in other racial or ethnic groups, will be necessary to further understand the role of MHC genes in an individual’s response to HCV therapy and the degree of genetic contribution to that response.