Most blood donors with anti-HCV have chronic hepatitis C regardless of their serum alanine aminotransferase levels. Donors with normal alanine aminotransferase levels and no HCV RNA in their serum generally have normal liver histologic findings or minimal changes and have probably recovered from HCV infection.

We examined hepatitis C virus genotypes in 98 American patients with chronic hepatitis C virus infection by means of two methods; restriction fragment length polymorphism analysis and line probe assay, which is based on type-specific sequence variations in the 5' untranslated region. Type 1 was present in 73 patients (74%), type 2 in 15 (15%), type 3 in 6 (6%) and type 4 in 1 (1%). Line probe assay further subdivided type 1 into 1a (n = 35) and type 1b (n = 37) and type 2 into type 2a (n = 6) and 2b (n = 9). Two patients (2%) had both restriction fragment length polymorphism and line probe assay evidence of dual infection (with types 1 and type 2) while another case had both type 1a and 1b by line probe assay. One patient was untypable by either technique. There was no correlation between infecting genotype and presumed cause, serum indexes of necroinflammatory activity, or age or sex of the patients studied or known duration of infection. Patients with type 2 hepatitis C virus had more severe liver disease histologically (p = 0.0027) compared with other genotypes but, paradoxically, had significantly lower levels of circulating hepatitis C virus RNA (12.1 +/- 12.8 x 10(5) genome equivalents/ml) than other types (36.4 +/- 44.8 x 10(5) genome equivalents/ml, p < 0.001). Response to interferon was less likely to be sustained in patients infected with type 1 than in those infected with other types (7% vs. 40%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

posed to direct peptide immunizations, this method allows As the chimpanzee, the only reliable animal model for host processing of newly synthesized viral proteins, which hepatitis C virus (HCV) infection, is impractical for early includes ensuring correct glycosylation and conformation of stage testing of HCV vaccine candidates, we have evaluthe proteins and proteolytic processing, known to be key facated the immune response in mice to an experimental tors in both humoral and cellular immune responses. Endogeplasmid based HCV vaccine. We used this system benous antigen processing may also lead to appropriate antigen cause DNA vaccines can be rapidly constructed without presentation by major histocompatibility complex class I and the necessity of large scale protein production and puriclass II molecules, an essential feature in T-cell recognition fication. In this preliminary study we tested the immune of the antigen. response in mice to HCV envelope glycoprotein, E2, inWhile the need for hepatitis C prevention is clear, a path duced by a eukaryotic expression plasmid. Protein exfor vaccine development is not. There exists support for the pression was monitored by immunofluorescence in concept that the hypervariable domain (HVR1) near the Ntransfected tissue culture cells. Each mouse was inocuterminus of E2 is an important neutralization site. However, lated intramuscular with 100 mg plasmid DNA and some genetic variability within this region may allow the virus to mice were boosted after 5 weeks. Among 12 BALB/C mice escape immune surveillance. 7-10 It has been difficult to show inoculated, 10 developed antibody to E2 by the second immune protection in either humans or experimentally inweek. The antibody levels increased steadily before fected chimpanzees. Cross-challenge experiments and even reaching a plateau in mice receiving the booster, but in rechallenge experiments in which chimpanzees were inocuthe nonboosted mice the antibody declined over time.lated several times with the same inoculum have shown that The serum from one mouse was tested against a series there is not solid immunity following infection. 11,12 This may of overlapping peptides covering most of E2. This serum be because of the presence of multiple quasispecies in the contained antibodies recognizing two distinct epitopes inoculum. On the other hand, experimental vaccines probeginning at amino acid 57 and amino acid 113 but no duced from synthetic envelope glycoproteins have been antibody was directed against peptides representing the shown to induce at least a low-level protection in chimpanhypervariable region of E2, antibody to which is thought zees against a homotypic challenge. 13 In addition, cellular to be important in HCV neutralization. We have shown immune responses to E2 have been reported 14,15 and these that the use of plasmid based vaccines can induce a spemay play a role in protection or recovery from hepatitis C cific immune response in mice against HCV antigens.virus (HCV) infection. This system should be useful as the fir...

Viruses from passages 9/10, 21, and 32 of a serially passaged human isolate of hepatitis A virus, strain HM-175, were partially sequenced and compared for their abilities to grow in cell cultures and to cause disease in primates. Viruses from all passages grew more efficiently in cell culture than did the wild-type virulent virus from which they were derived, and all displayed some degree of attenuation of virulence for primates. Within the 5' noncoding region and the 2B2C region of the HAV genome, passage 9/10 virus differed in sequence from wild-type at a single and novel position in the 2C gene, while the sequence of the passage 32 virus was almost identical to that of a fully attenuated passage 35 virus. Passage 21 viruses were found to consist of a mixture of viruses which included all but two of the 13 mutations present in the sequenced regions of the virus from passage 32.