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Nucleotide (nt) sequences of the X region of more than 130 hepatitis B virus (HBV) isolates were determined and derived from patients with a variety of clinical features. Correlation of nt substitutions with clinicopathological characteristics was attempted. The X region (465nt) is crucial for the replication and expression of HBV because the X protein transactivates the HBV genes and this region contains the core promoter, enhancer II, and two direct repeats. There are several mutational hotspots, some of which seem to relate to immunological epitopes of the X protein. Two kinds of mutations which have important clinical significances were found. One is an 8-nt deletion between nt 1770 and 1777, which truncates 20 amino acids from the carboxyl terminus of the X protein. This deletion leads to the suppression of replication and expression of HBV DNA, resulting in immunoserological marker (HBsAg) negativity. This silent HBV infection is responsible for the majority of non-A to non-E hepatitis. The other mutation substituting T for C (nt 1655), T for A (nt 1764) and A for G (nt 1766) seems to relate to fulminant hepatitis. Further sequencing studies and in vitro mutagenesis experiments will clarify the significance of other mutations of the X region.