Follow-up of hepatitis C virus infection in chimpanzees: determination of viraemia and specific humoral immune response

Abstract

Chimpanzees were inoculated intravenously with the H strain of hepatitis C virus (HCV), and analysed for viraemia using the polymerase chain reaction and for a humoral immune response using first and second generation anti-HCV ELISAs and an immunoblot assay (4-RIBA). In all seven chimpanzees studied, viraemia occurred several weeks before a significant increase in serum alanine transferase (ALT) activity, whereas the first circulating anti-HCV antibodies became detectable at the time of significant increase in ALT levels, provided the second generation ELISA or 4-RIBA was used. On the basis of the duration of viraemia the chimpanzees studied could be assigned to two different groups: those in which viraemia disappeared in conjunction with or shortly after seroconversion, and those remaining viraemic for many weeks after the appearance of antibodies. The clearance of HCV from the circulation did not correlate with the antibody pattern determined using 4-RIBA, i.e. the HCV-specific assays currently available do not enable us to predict whether an infected chimpanzee will develop persistent viraemia. Only two of the seven chimpanzees analysed developed anti-core protein (c-22) antibodies, which appeared at the same time as the first ALT peak, whereas all animals developed antibodies to the non-structural protein, c-33, and these antibodies persisted.Only after the hepatitis C virus (HCV) genome had been cloned by Choo et al. (1989) was it possible to develop specific assays, such as ELISA, recombinant immunoblot assay (RIBA) and the polymerase chain reaction (PCR), to diagnose HCV infection. These assays can now be used to study the development of viraemia and the specific immune response in HCV-infected chimpanzees, the only experimental animals sensitive to HCV. Shimizu et al. (1990) published a study on the early stages of HCV infection in chimpanzees, focusing on the determination of viraemia by PCR. Their study of the humoral immune response was limited to the first generation assay, detecting antibodies to c-100 only, a recombinant polypeptide that represents part of a nonstructural HCV protein.We have extended these studies on HCV viraemia and the specific immune response in chimpanzees using the assays developed most recently. The seven animals investigated were positive (HCV-infected) controls from studies in which the inactivation of HCV by various methods included in the procedures for manufacturing human plasma proteins for therapeutic use had been studied (Mauler et aL, 1987). The HCV isolate used for spiking the source plasma preparations in these studies was the human H pool plasma, now designated H strain (Ogata etal., 1991). Chimpanzees inoculated with HCVspiked human plasma or plasma derivatives were regarded as being HCV-infected when the serum alanine transferase (ALT) activity increased significantly, and infections with hepatitis A virus (HAV), hepatitis B virus (HBV) and the human herpesviruses, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), could be excluded.We demonstrate that the chi...

Protective Immune Response to Hepatitis C Virus in Chimpanzees Rechallenged Following Clearance of Primary Infection

“…5 In contrast, antibody responses to HCV structural proteins are observed less frequently in chimpanzees than in humans for reasons not understood. [5][6][7][8][9][10][11] Studies in chimpanzees have revealed that antibody neutralization of HCV is not easily attained. 12,13 Recently, Cooper et al observed that strong antibody responses to HCV proteins were not necessary for viral clearance in HCV-inoculated chimpanzees.…”

Differences in HCV antibody patterns in haemodialysis patients infected with the same virus isolate

“…Moreover, it has been reported that chimpanzees who were infected by the same HCV isolate elicited different antibody responses. Such studies, however, focused only on recombinant envelope proteins which have been supposed to be targets for a protective immune response [van Doorn et al, 1997] or merely monitored the development of anti-HCV antibodies as evidence for the infection of an animal [Hilfenhaus et al, 1992]. In the present report we show that in HD patients the pattern of antibody response against various antigens is not dependent on the infecting isolate but varies from patient to patient.…”

Hepatitis C: Seven Years After the Discovery of the Causative Agent

“…Persistent viraemia with progression of chronicity; 3. Intermittent viraemia characterised by initial loss of serum HCV-RNA but which may recur periodically after some weeks and even some months (62,63). Development of liver cirrhosis and hepatocellular carcinoma has been documented in chronic HCV infection (64)(65)(66).…”