Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization.

Abstract

Hepatitis C virus (HCV) is the most important etiologic agent of non-A, non-B hepatitis and is a major cause of chronic liver disease and hepatocellular carcinoma. Development ofan effective vaccine would be the most practical method for prevention of the infection, but whether infection with HCV elicits protective immunity in the host is unclear. Neutralization of HCV in vitro was attempted with plasma of a chronically infected patient, and the residual infectivity was evaluated by inoculation of eight seronegative chimpanzees. The source of HCV was plasma obtained from a patient during the acute phase of posttransfsion non-A, non-B hepatitis, which had previously been titered for infectivity in chimpanzees. Neutralization was achieved with plasma obtained from the same patient 2 yr after the onset of primary infection but not with plasma obtained 11 yr later, although both plasmas contained antibodies against nonstructural and structural (including envelope) HCV proteins. Analysis of sequential viral isolates from the same patient revealed significant genetic divergence as early as 2 yr after infection. However, the HCV recovered from the patient 2 yr after the infection had a striking sequence similarity with the HCV recovered from one of the chimpanzees inoculated with the acute-phase virus, suggesting that the progenitor of the new strain was already present 2 yr earlier. This evidence, together with the different sequences of HCV recovered from the chimpanzees that received the same inoculum, confirms that HCV is present in vivo as a quasispecies. These results provide experimental evidence in vivo that HCV infection elicits a neutralizing antibody response in humans but suggest that such antibodies are isolate-specific. This result raises concerns for the development of a broadly reactive vaccine against HCV.

Immune responses during acute and chronic infection with hepatitis C virus

“…Whether or not the typical antibodies measured in these studies conferred or was a marker of sterilizing immunity is controversial. In vivo studies in chimpanzees showed that the HCV-specific antibodies, specific for the HVR and with in vitro neutralizing ability, had protective effects against HCV infection [65]. On the other hand, other studies demonstrated that anti-HVR antibodies could not confer protective immunity against reinfection with homologous or heterologous strains [66; 67].…”

Acute hepatitis C virus infection: A chronic problem

“…Two HVRs (HVR1 and HVR2) in the E2 envelope glycoprotein have been identified. 52,53 At least 1 study has suggested that the early appearance of HVR1 antibodies is associated with an acute self-limiting HCV infection. 54 Additionally, mutations within certain regions, especially the E2 HVR, have been associated with the emergence of virus resistance to neutralization and the persistence of infection.…”

Experimental models for hepatitis C viral infection #

“…In vitro preincubation of a standardized infectious HCV inoculum with the putative neutralizing serum or purified immunoglobulin G (IgG) showed that some challenged naïve chimpanzees were protected from HCV infection. 51,52 Although these results heralded enthusiasm on possible passive immunization strategies against HCV, the step toward clinical application proved to be more difficult. Postexposure prophylaxis of one chimpanzee with high amounts of anti-HCV IgG at 1 hour after its experimental inoculation did not prevent HCV infection.…”