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least 6 major types and 40 subtypes have been identified around the world. The 1A and 1B subtypes account for most infections in the United States.

The genome consists of about 10,000 nucleotides, with a 5' terminal iris and an internal ribosome entry site. It makes a large polyprotein that is cleaved post-translationally and co-translationally by a combination of host enzymes and viral proteases. It seems that the host signal peptidase is primarily involved in processing the nuclear capsid and the two envelope glycoproteins (gpE1 and gpE2). The presumed nonstructural proteins (NS) appear to be processed by the action of two viral proteases, one in the NS3 domain that is a trypsin-like protease, and another that spans the NS2 and NS3 genes that appears to be a metallic protease.

Immunology. Preliminary work on the correlates of immunity have shown that peripheral CD4-positive T-cells respond to HCV nonstructural protein 3 (NS3) very early in the infection, and that this response persists following recovery. In chronic patients, however, there is very little T-cell response. There is evidence that the protective immune response is short-lived and weak, at best. For example, a study of polytransfused thalassemic children found that patients who normalized after an initial episode of acute hepatitis nevertheless developed a second infection that progressed to chronic persistent hepatitis. Both infections involved the HCV-1-B subtype.

Viral Persistence. HCV is remarkably adept at persisting in the host in the face of an apparently substantial immune response. In the livers of about 50 percent of patients with chronic hepatitis, researchers are able to identify CTLs of varying specificity to either structural protein or to nonstructural proteins in the polyprotein precursor. CTLs also infiltrate the livers of chimpanzees with chronic infections. It is not known how the virus persists in the face of such a response. One theory is that HCV has evolved a mechanism for abrogating a lymphokine action; another is that the virus inhibits CTL induction in vivo. It is possible that there may be immune-privilege sites in the host that have not been identified.

Another theory is based on recent work suggesting that there are CTL escape mutants in chronically infected chimpanzees. An otherwise conserved epitope in nonstructural protein 3 (NS3), which is the target for a strong CTL response, mutated over time, leading researchers to speculate that escape variants might emerge.

Immune Escape. Virtually every patient with chronic non-A and non-B hepatitis, whether from transfusion or IV drug use, has circulating levels of antibodies to the envelope glycoproteins gpE1 and gpE2. HCV can be difficult to grow in vitro, but work done in Japan suggests that the virus mutates over time to evade this humeral immune response. Using an RNA binding assay, researchers were able to show that serum taken from 1978 to 1982 contained antibodies that would neutralize HCV taken in 1977. In the same patient, however, the antibodies that neutralized the 1977 virus did not neutralize virus



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