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taken in 1990. By 1991, the patient did have antibodies to neutralize the 1990 virus.

This finding was consistent with the process of immune escape. Further research revealed that there were multiple mutations between the 1977 and 1990 virus, as would be expected from an RNA virus. The rate of mutation is at the level of about .01 percent per nucleotide per year, but there was a cluster of mutations in a very small region at the terminus of gpE2. These mutations, between residues 395 and 487, resulted in a variety of nonconservative amino acid changes.

This region appears to be under severe immune pressure, and isolates of HCV from patients around the world show that the end terminal region of gpE2 is different in virtually every isolate, often involving nonconservative neoacid changes. This region is a target for B-lymphocytes, and a recent study in Germany indicates that antibodies to this end-terminal hypervariable region prevented binding of HCV inoculum to human fibroblasts. This leads researchers to speculate that the end terminus of gpE2 may be the principal neutralizing domain of the virus. Given the difficulty of growing HCV in vitro, it will take some time to confirm this.

Vaccine Development. Many of the approaches that might be pursued aren’t yet possible because of the early stage of the research on HCV.

The virus is very difficult to grow in tissue culture, and the only animal model is the chimpanzee, so it will also be difficult to attenuate the virus. There are few subunits circulating in these patients. As a result, there are only three approaches available at present: recombinant subunit vaccines, naked DNA vaccines, and vector DNA vaccines. Researchers are pursuing all three approaches in order to produce a very complete immune response. The following discussion focuses on subunit vaccines.

The subunit vaccine that has been tested in chimpanzees was derived by expressing the viral gpE1, gpE2, and NS-2 genes in mammalian cells, initially through the use of recombinant vaccinia donated by NIH. The pure subunits are combined with an adjuvant called MF-59 that has been used extensively in the herpes clinical trials. Usually the chimpanzee was immunized first with wildtype vaccinia, to rule out any residual live recombinant vaccinia in any subsequent protection, and then given up to 40 micrograms of subunits at months 0, 1, and 7. A total of 3 weeks after the final boost the animal was challenged with 10 infectious doses of homologous virus.

Out of 12 experimental chimpanzees, 5 were completely protected—there was no trace of viral RNA in the plasma, in the liver, or in the PBLs. Of the other 7 animals, 5 went through acute infection and resolved, after which there was no trace of virus. Only 2 experimental chimpanzees went on to develop chronic infection, and one of these had ameliorated acute hepatitis. By contrast, out of 7 unimmunized controls that were challenged with virus, 6 developed chronic infection following acute hepatitis and only one experienced resolution of the infection.



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