Future Directions

As more antiviral agents for treatment of HBV are developed, the key surrogate endpoints that will be used are suppression of serum HBV DNA levels and prevention of the development of antiviral resistance. Long-term suppression of viral replication is associated with both biochemical and histological improvement in liver disease. These factors make the development, clinical evaluation, and availability of reliable, standardized quantitative tests for HBV DNA a major priority for the near future. Similarly, increased emphasis will be placed on characterization of drug resistance mutants and HBV genotyping to assist with clinical management of patients as new drugs are developed.

HEPATITIS C VIRUS

HCV is an RNA virus with a positive-sense, single-stranded genome of approximately 9500 nt encoding a single polyprotein of about 3000 amino acids. The long open reading frame is flanked at each end by a short untranslated region (UTR). The genome structure is most similar to viruses of the family Flaviviridae, which includes many of the arthropod-borne viruses. As in other flaviviruses, the three N-terminal proteins of HCV (core, envelope 1, and envelope 2) are probably structural and the four C-terminal proteins (nonstructural 2, 3, 4, and 5) are thought to function in viral replication.

The 5' UTR is a highly conserved region of 341 nt and has a complex secondary structure. It contains an internal ribosome entry site and presumably is important in the translation of the long open reading frame. The 3' UTR contains a short region that varies in sequence and length, followed by a polypyrimidine stretch of variable length, and finally a highly conserved sequence of 98 nt, which constitutes the terminus of the genome. The function of the 3' UTR is not known but is thought to be essential for viral replication.

The envelope 1 (E1) and 2 (E2) regions of HCV are the most variable regions within the genome at both the nucleotide and amino acid levels. Two regions in the E2, called hypervariable regions 1 and 2 (HVR1 and HRV2), show extreme sequence variability, which is thought to result from selective pressure by antiviral antibodies. E2 also contains the binding site for CD81, the putative HCV receptor or coreceptor.

The nonstructural regions 2 (NS2) and 3 (NS3) contain a Zn-dependent autoprotease that cleaves the polyprotein at the NS2-NS3 junction. The aminoterminal portion of the NS3 protein also is a serine protease that cleaves the polyprotein at several sites. The carboxyterminal portion of the NS3 protein has helicase activity, which is important for HCV replication. The NS4A protein is a cofactor for NS3 serine protease. The NS5B region encodes the RNA-dependent RNA polymerase, which replicates the viral genome. A region in NS5A has been linked to response to IFNa and is therefore called the IFNa-sensitivity determining region (ISDR).

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