Influence of antibodies to the hypervariable region of E2/NS1 glycoprotein on the selective replication of hepatitis C virus in chimpanzees.

A human plasma (inoculum one) containing hepatitis C virus (HCV) was passaged through eight chimpanzees in three generations. Of 10 HCV clones propagated from it, 7 were different in respect to the hypervariable region of E2/NS1 glycoprotein and they were named clones A, B, C, etc. A chimpanzee received inoculum one, and clone A accounted for 7 of the 10 clones from his acute-phase plasma (inoculum two). Five chimpanzees received inoculum two, and clone A accounted for 5 to 9 of the 10 clones each from their preacute plasma, which were pooled to make inoculum three. Of 10 HCV clones from inoculum three, 4 were A, 5 were B/B', and the remaining 1 was C. Two chimpanzees received inoculum three or its CsCl fraction, and all 40 clones from their acute-phase plasma were A. Thus, clone A in inoculum one was selected by chimpanzees during three passages. HCV virions in the three inocula were separated into free and immunoglobulin-bound forms by sucrose density fractionation. HCV virions in inocula one and two were heterogeneous in the sequence of hypervariable region and predominantly free of immunoglobulins. By contrast, inoculum three contained both free virions of predominantly A and immunoglobulin-bound virions which were heterogeneous. Antibodies to the hypervariable region were determined by enzyme immunoassays with overlapping synthetic decapeptides. Antibodies to clone A were detected in one chimpanzee who received inoculum two, and those to clones B and C in two chimpanzees including him and in inoculum three. Antibodies were not detectable in inoculum one or two or in the other chimpanzees. These results indicate that antibodies to the hypervariable region of E2/NS1 glycoprotein would be protective and contribute toward the selective replication of HCV in chimpanzees.