The C1653T, T1674C/G, G1719T, A1727T, C1730G, and C1799G mutations were located in the core promoter region (nt 1591 to nt 1882) (45), resulting in amino acid substitutions at H94Y, S101P, V116L, K118N, D119E, and S142C, respectively, in the C-terminal region of HBx. The C1653T mutation also changes the box-�� binding Temsirolimus site for the transcription factor C/EBP, which enhances the activity of the core promoter and viral replication (46). The C1673T mutation does not cause an amino acid substitution but binds to transcription factors such as C/EBP (47), resulting in possible alterations in viral activities. The same is true for the A1846T mutation (11). The A31T, G105C, A135C, and G147C mutations lead to amino acid substitutions at E133D, G158A/V, N168T, and G172A, respectively, in the pre-S2 region.

The C10A, T49A, and C109A mutations do not cause corresponding amino acid substitutions. They might affect viral activities by altering potential transcription factor binding sites (48). The G1896A mutation introduces a stop codon, W28Stop, in the pre-C region, which impairs HBeAg expression (46). The HBV mutations in the core promoter region fall in HLA-A2-restricted epitopes, while A31T and T49A mutations in the pre-S2 region fall in the restricted epitopes of HLA-A2/A3 and HLA-DR1/DR2 as well as HLA-A2 and HLA-DR1, respectively (49). It is unknown if the HLA-DP polymorphism-affected HBV mutations form the restricted epitopes of HLA-DP.

The HLA-DP genotypes promoting HBV persistence were generally associated with a higher prevalence of HBV mutations increasing HCC risk, indicating that they may play an active role in maintaining an evolutionary microenvironment for the selection of these disease-related HBV mutations. This study enrolled HCC-free HBV-infected subjects around 50 years of age. Some of them will develop HCC because HCC incidence in HBV-infected subjects increases sharply after 60 years of age. HCC-associated HBV mutations are usually generated years before HCC occurs (9, 13�C16). Thus, HLA polymorphisms might affect the occurrence of AV-951 HCC via regulating immunoselection of HBV mutations. Interestingly, the associations of the HBV mutations with the risks of HC and HCC were significantly affected by the HLA-DP polymorphisms (Tables 6 and and7).7). Significant effects of the G1896A, C1653T, and T1674C/G mutations on HC risk were significant only for those with the HLA-DP polymorphisms promoting HBV persistence and not for those with the ones promoting HBV clearance. The interactions of these mutations with the HLA-DP polymorphisms promoting HBV clearance were protective for HC.