In Vivo And In Vitro Studies Of Hepatitis E Virus

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Abstract

We have passaged a strain of HEV from serum collected from wild rats in Los Angeles to Sprague-Dawley laboratory rats but the infection rate is very low, suggesting the virus is replicating inefficiently. We also partially sequenced a new genotype 3 strain of HEV we isolated from a patient at NIH: this virus was closely related to the virus we previously showed was ubiquitous in swine in the USA. Swine may be a zoonotic reservoir of HEV. We collaborated in a large serosurvey of US swine handlers and demonstrated that they had a slightly higher risk of infection than did normal blood donors. Two baculovirus-expressed recombinant capsid protein vaccines we developed were compared for efficacy in rhesus macaques and a GLP challenge study in macaques of the most effective one was completed. The US Army began phase II/III clinical trials of this vaccine candidate in Nepal this summer. We have developed a baculovirus expression system for a nonstructural protein of HEV and are attempting to develop an ELISA based on it for eventual use in evaluating vaccine efficacy. We have constructed two cDNA clones of HEV which differ by a single nucleotide. Transcripts from one cDNA clone encoded a virus which infected, but was attenuated for chimpanzees but it did not infect rhesus monkeys. Transcripts of the second recombinant virus infected rhesus monkeys in addition to chimpanzees and caused acute hepatitis in both species. The single mutation differentiating the two viruses identified the location of a cis-reacting element. We also confirmed our previous demonstration that HEV genomes have a 5' cap structure and showed that the cap was required for infection of primates.