Sequence divergence of cloned HCV genome from patients indicates several genotypes and a series of subtypes for this virus. An HCV genotypes 1a and 1b are predominant in patients with chronic hepatitis C. The virus genome contains a linear, positive-strand RNA molecule of ∼9500 nucleotides, which encodes a single polyprotein precursor of ∼3000 amino acid residues .
This polyprotein is cleaved by both host and viral proteases to generate at least 10 individual proteins (Fig. 1): Core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B. The structural proteins (Core, E1, E2/p7) are located in the amino-terminal one-fourth of the polyprotein. The genomic region encoding the core protein encompasses amino acids 1–191. Physical association of the core protein with E1 and E2 glycoproteins, most likely taking place in the ER membrane, may have a role in virus morphogenesis. In vitro translation assay from cloned genomic region in the presence or absence of microsomal membrane facilitated the initial characterization of core polypeptides [7,8]. In the absence of microsomal membrane, a polypeptide of ∼22 kDa is the primary translated product. Additional polypeptides of higher molecular mass also appear, probably representing complex oligomeric aggregates of core protein. However, in the presence of microsomal membrane, a change in the polypeptide profile of the in vitro translated product is observed. This change is likely derived from a post-translational proteolytic cleavage of the signal peptide located at the carboxy-terminal of the unprocessed core protein. Multimerization of core protein occurs when expressed as recombinant protein. Three different core protein products of ∼21, 19 and 16 kDa are generated from HCV genotype 1a [9,10]. The ∼16-kDa core protein exists as co-amino-terminal sequence of the ∼21-kDa protein, but lacks the carboxy-terminal sequence of ∼21-kDa protein. The expression of core protein as a ∼16-kDa species is associated with a Lys-9 codon substitution in HCV genotype 1a; however the mechanism for generation of this protein product remains to be understood. On the other hand, a single polypeptide of ∼21 kDa or two forms of the core protein, ∼21 kDa and 19 kDa, are generated from HCV genotype 1b. Missense mutations at codons 9–11 can occur during chronic HCV infection resulting in expression of an ∼16-kDa core protein , and an analysis of 10 cases of individuals with HCV-related HCC revealed that three patients have these codon mutations in the core gene. Higher sequence variations within the core are apparent in tumor as compared to non-tumor tissues , and the appearance of in-frame stop codons, and deletions leading to frameshifts occur in HCV-associated HCC patients. The secondary or tertiary structure of HCV core protein might be important for specific interaction with viral genomic RNA , although the precise length of the core protein species for its likely role in encapsidation of viral RNA is yet to be determined. The core protein of HCV genotype 1a primarily localizes in the cytoplasm [9,10]. However, nuclear localization of the core protein has also been shown in gene-transfected mammalian cells  and in the hepatocytes of HCV-infected patients . The carboxy-terminal truncated core protein has been implicated for nuclear localization in some studies. The core protein from HCV genotype 1b accumulates in the nuclei and mitochondria of transgenic mice . Thus, it is not clear at present whether nuclear localization of core protein occurs as a result of frameshift (Jing-Hsiung Ou, personal communication) or truncation of the carboxy-terminus.