Transmission of Hepatitis E Virus from Rabbits to Cynomolgus Macaques

Peng Liu, Qiu-Ning Bu, Ling Wang

, Jian Han, Ren-Jie Du, Ya-Xin Lei, Yu-Qing Ouyang, Jie Li, Yong-Hong Zhu, Feng-Min Lu, and Hui Zhuang

Author affiliations: Peking University Health Science Center, Beijing, People’s Republic of China

Abstract

The recent discovery of hepatitis E virus (HEV) strains in rabbits in the People’s Republic of China and the United States revealed that rabbits are another noteworthy reservoir of HEV. However, whether HEV from rabbits can infect humans is unclear. To study the zoonotic potential for and pathogenesis of rabbit HEV, we infected 2 cynomolgus macaques and 2 rabbits with an HEV strain from rabbits in China. Typical hepatitis developed in both monkeys; they exhibited elevated liver enzymes, viremia, virus shedding in fecal specimens, and seroconversion. Comparison of the complete genome sequence of HEV passed in the macaques with that of the inoculum showed 99.8% nucleotide identity. Rabbit HEV RNA (positive- and negative-stranded) was detectable in various tissues from the experimentally infected rabbits, indicating that extrahepatic replication may be common. Thus, HEV is transmissible from rabbits to cynomolgus macaques, which suggests that rabbits may be a new source of human HEV infection.

Hepatitis E virus (HEV) is the causative agent of acute hepatitis E, which is endemic to many developing countries and occurs sporadically in some industrialized countries. HEV is a small nonenveloped virus with a positive-sense single-stranded RNA genome of ≈7.2 kb; it is currently classified as the sole member of the genus Hepevirus, family Hepeviridae (1). Thus far, at least 4 genotypes, which comprise a single serotype, of HEV have been identified in mammals: genotypes 1 and 2 are restricted to strains that infect humans, and genotypes 3 and 4 are zoonotic (2). More recently, a putative fifth HEV genotype was identified in wild boars in Japan (3). HEV from chickens, which is phylogenetically distinct from HEV from mammals, is likely to be classified as a new genus within the family Hepeviridae (4).
The zoonotic nature of HEV was first confirmed in 1997 with the identification of HEV isolates in swine in the United States, which were most closely related to an isolate of HEV from a person in the United States, and this isolate could experimentally infect nonhuman primates (5,6). Zoonotic transmission of HEV was further substantiated with the demonstration of HEV infection in persons after they ate undercooked infected meat from wild boars and wild deer (7,8). Antibodies against HEV have been detected in numerous animal species, including dogs, cats, sheep, goats, horses, cattle, bison, and rats; and HEV strains have been genetically identified from domestic and wild pigs, chickens, deer, mongooses, and rabbits (4,9). The recent discoveries of HEV-like viruses in rats and fish have further broadened understanding of the host range and diversity of HEV (10–12).
The first strain of rabbit HEV was isolated from Rex Rabbits on 2 rabbit farms in Gansu, People’s Republic of China (13). Additional studies indicated that rabbit HEV was prevalent among various breeds of farmed rabbits throughout much of China, and the prevalence of antibodies against HEV was 57.0% in Lanzhou and 54.6% in Beijing (13–15). Rabbit HEV has also been isolated from rabbits in Virginia, USA, which showed a high prevalence of antibodies against HEV (36%) and HEV RNA (16.5%) (16). Phylogenetic analyses revealed that rabbit HEV was most closely related to genotype 3 HEV, which has been confirmed to infect humans. Furthermore, a recent study indicated that rabbit HEV is antigenically related to the other known animal strains of HEV and is experimentally transmissible to swine (17). However, to our knowledge, no study had determined the zoonotic potential of rabbit HEV. Therefore, in this study, we endeavored to ascertain whether rabbit HEV can cross species barriers and infect nonhuman primates and to further clarify the pathogenesis and replication of rabbit HEV in its natural host.