Cross‐protection of hepatitis E virus genotypes 1 and 4 in rhesus macaques

Abstract

The purpose of this study was to determine cross-protection between HEV genotypes 1 and 4, which are prevalent in China. Fecal suspensions of genotypes 1 and 4 from patients, as well as genotype 4 from swine, were inoculated intravenously into rhesus macaques. Each inoculum contained 5 x 10(4) genome equivalents of HEV. After infection, serum and fecal samples were collected serially and the levels of alanine aminotransferase (ALT) and anti-HEV IgG and IgM in sera, and HEV RNA in fecal samples, were measured. Liver biopsies were carried out. All the infected monkeys (12/12) developed anti-HEV IgG and exhibited fecal shedding of virus. IgM was detected in 11 of 12, and ALT elevation occurred about 2-6 weeks post-inoculation in 10 of 12, infected monkeys. Hepatic histopathology was consistent with acute viral hepatitis and the ORF2 antigen of HEV was detected in the granular cytoplasm of hepatocytes by immunohistochemistry. After recovery from their initial HEV infection, the monkeys were challenged with a heterologous genotype or heterologous source of HEV and monitored for hepatitis and fecal shedding. Previous infection with HEV completely or partially protected against subsequent challenge with a heterologous virus, because 7 of 11 monkeys did not develop HEV infection or shed virus in the feces, and none of them developed hepatitis or exhibited ALT elevation or liver biopsy findings of hepatitis. In conclusion, previous HEV infection may give rise to cross-genotype and cross-host-species protection.

Host Immune Status and Response to Hepatitis E Virus Infection

“…Huang et al (209) inoculated 11 macaques with fecal suspensions containing HEV genotypes 1 (from humans) and 4 (from humans and swine) and demonstrated protection against acute hepatitis (i.e., elevation of liver enzymes) upon later cross-challenge. However, about half of these monkeys (6/11 in total) showed evidence of fecal shedding, transient IgM seropositivity, or increased IgG production following repeat inoculation (209).…”

“…Huang et al (209) inoculated 11 macaques with fecal suspensions containing HEV genotypes 1 (from humans) and 4 (from humans and swine) and demonstrated protection against acute hepatitis (i.e., elevation of liver enzymes) upon later cross-challenge. However, about half of these monkeys (6/11 in total) showed evidence of fecal shedding, transient IgM seropositivity, or increased IgG production following repeat inoculation (209). Similarly, follow-up of the macaques experimentally infected by Arankalle et al (188) documented a decline in anti-HEV IgG titers over the course of 5 to 7 years at a rate that "was not a function of the number of exposures to HEV, and probably represented biological variations among individual monkeys" (191).…”

Experimental Infection of Rabbits with Rabbit and Genotypes 1 and 4 Hepatitis E Viruses

“…Although pigs could be used as an experimental model of genotypes 3 and 4 HEV infection but cannot be infected with genotype 1 HEV and difficulties in handling, manipulating, and housing [18], [17], [19] and above all, the inability to emulate human disease caused by genotypes 3 and 4, limit the value of this animal model for studying the disease aspect of HEV infection. A number of non-human primate species, such as cynomolgus macaques, rhesus, owl, and African green monkeys and chimpanzees are susceptible to HEV infection and some have been used successfully as animal models of hepatitis E [20], [21], [22], [23], [24], [25]. The most valuable are macaques because the disease is reproduced readily in them.…”

Hepatitis E Virus

“…pigs, deer and mongoose with 10 subtypes a-j) and genotype 4 (HEV-4, isolates from patients with sporadic hepatitis in Asia and from pigs with 7 subtypes a-g). Neutralisation of viruses in cell culture systems and cross-protection experiments in animals imply that HEV-1-4 form a single serotype [22,23,24]. …”