With the progression of chronic infection, especially during HBeAg seroconversion, HBV mutations gradually occur (21). HBV reverse transcriptase lacks proofreading activity, resulting in an estimated mutation rate of 4.57 �� 10?5 nucleotide (nt) substitutions per site per year (22). Inflammatory factors promote Imatinib Mesylate HBV mutations, at least partially, via activating cytidine deaminases (23, 24). Insufficient immune responses elicited by HBV antigens select disease-related HBV mutations during the long-term evolutionary process. Only the HBV strains/variants best adapted to the host immune system will survive and thrive in liver. HBV accumulates mutations via minimizing the total number of epitopes recognized by CD8+ T cells, particularly in the HBx and the pre-S1/pre-S2/S regions, to avoid immune clearance (25).
These HBV mutations are probably selected via virus-immune interactions in the inflammatory microenvironment. Human leukocyte antigen (HLA) plays a pivotal role in the immune response against HBV infection. The complexes of HLA class I molecules and HBV-specific antigen peptides are recognized by CD8+ cytotoxic lymphocytes and trigger hepatocytolysis to eliminate HBV-infected hepatocytes. HLA class II molecules are classified into three isotypes: HLA-DR, -DQ, and -DP. The importance of polymorphic residues in HBV peptide binding and T cell recognition, mainly in the HLA-DR and HLA-DQ molecules, has been intensely studied. However, less is known about HLA-DP molecules.
A recent genome-wide association study (GWAS) revealed that 11 single-nucleotide polymorphisms (SNPs) in the HLA-DPA1 and HLA-DPB1 regions were significantly associated with HBV persistence in Asians (26). Subsequent studies further reported that some of the 11 SNPs were significantly associated with HBV persistence/clearance in Eastern Asians (27�C32). The associations of HLA-DP SNPs and HBV-caused advanced liver diseases have not been fully elucidated, except for one study reporting a borderline-significant effect of rs3077 on genetic susceptibility to HCC (28). The effects of HLA SNPs on the generation of HC- or HCC-related HBV mutations and their interactions on the outcomes of HBV infection have not been reported. In this study, we investigated the associations of HLA-DP SNPs with the persistence/clearance of HBV and the generation of HC- and HCC-related HBV mutations in subjects chronically infected with genotype B or genotype C.
The effects of interactions of HBV mutations with HLA SNPs on the risks of HC and HCC were also evaluated. This study highlights the effect of HLA-DP polymorphisms on the evolution AV-951 of the HBV genome during chronic infection and also suggests that HBV mutants affect the occurrence of HC and HCC via interacting with HLA-DP polymorphisms. MATERIALS AND METHODS Study participants.