A novel phenotypic assay of hepatitis B virus polymerase with extensive site-specific mutagenesis
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A common reason for drug failure during long-term treatment of chronic hepatitis B with nucleot(s)ide analogues (NUCs) is the emergence of drug resistance (Das et al., 2001). Most primary NUCs-resistant mutations identified in clinical samples have been limited to a minority of amino acids (usually less than three kinds) that replace the wild type amino acid at a single site (Kirishima et al., 2002). However, each site should, theoretically, have the same opportunity to be mutated to any of the 19 amino acids other than that of the wild type during the DNA synthesis catalyzed by the error-prone viral polymerase (Bartholomeusz et al., 2004). Therefore, precisely how these undiscovered possible mutations influence the viral phenotype is an interesting research question. To address this issue, Baldick et al.constructed a comprehensive panel of clones containing every possible amino acid at the three primary amino acid positions related to entecavir resistance (rtT184,...