Infectivity titration of a prototype strain of hepatitis E virus in cynomolgus monkeys

Tsarev, Sergei A.; Tsareva, Tatiana S.; Emerson, Suzanne U.; Yarbough, Patrice O.; Legters, Llewellyn J.; Moskal, Thomas J.; Purcell, Robert H.

doi:10.1002/jmv.1890430207

Cited by 128 publications

(103 citation statements)

References 25 publications

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“…One rhesus monkey seroconverted at 5 weeks postinoculation and the other at 8 weeks. The time to seroconversion in these two transfected rhesus monkeys was similar to those observed previously when the Sar-55 virus in a clinical sample was titrated in cynomolgus macaques, a species used interchangeably with rhesus macaques for HEV studies (16). The titration study demonstrated that time to seroconversion increased as the dose of virus was decreased, but the severity of hepatitis generally decreased as the dose was decreased.…”

Section: Discussionsupporting

confidence: 82%

“…Animals infected with HEV can develop hepatitis, as demonstrated by elevation of serum liver enzymes and appearance of histopathological changes in the liver. The severity of the hepatitis appears to depend on the initial viral load, and a low dose of virus can infect without causing overt disease (16). Viremia does occur, and virus can be detected also in bile and feces.…”

Section: H Epatitis E Virus (Hev) Is An Unclassified Nonenvelopedmentioning

confidence: 99%

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Recombinant hepatitis E virus genomes infectious for primates: Importance of capping and discovery of a cis-reactive element

Emerson

Zhang

Meng

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

164

185

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Hepatitis E virus recombinant genomes transcribed in vitro from two cDNA clones differing by two nucleotides were infectious for chimpanzees. However, one cDNA clone encoded a virus that was attenuated for chimpanzees and unable to infect rhesus monkeys. The second cDNA clone encoded a virus that infected both chimpanzees and rhesus monkeys and caused acute hepatitis in both. One mutation differentiating the two clones identified a cisreactive element that appeared to overlap the 3 end of the capsid gene and part of the 3 noncoding region. Capping of the RNA transcripts was essential for infectivity.

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Section: Discussionsupporting

confidence: 82%

Section: H Epatitis E Virus (Hev) Is An Unclassified Nonenvelopedmentioning

confidence: 99%

Recombinant hepatitis E virus genomes infectious for primates: Importance of capping and discovery of a cis-reactive element

Emerson

Zhang

Meng

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

164

185

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“…The appearance of viremia and shedding of virus in feces is apparently dose dependent, as virus shedding in blood and feces appeared earlier in chickens inoculated with a higher dose than in those inoculated with a lower dose. This observation is consistent with those from the infectivity titration results in experiments with monkeys inoculated with human HEV (32).…”

Section: Discussionsupporting

confidence: 91%

Generation and Infectivity Titration of an Infectious Stock of Avian Hepatitis E Virus (HEV) in Chickens and Cross-Species Infection of Turkeys with Avian HEV

et al. 2004

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Avian hepatitis E virus (HEV), a novel virus identified from chickens with hepatitis-splenomegaly syndrome in the United States, is genetically and antigenically related to human HEV. In order to further characterize avian HEV, an infectious viral stock with a known infectious titer must be generated, as HEV cannot be propagated in vitro. Bile and feces collected from specific-pathogen-free (SPF) chickens experimentally infected with avian HEV were used to prepare an avian HEV infectious stock as a 10% suspension of positive fecal and bile samples in phosphate-buffered saline. The infectivity titer of this infectious stock was determined by inoculating 1-week-old SPF chickens intravenously with 200 l of each of serial 10-fold dilutions (10 ؊2 to 10 ؊6 ) of the avian HEV stock (two chickens were inoculated with each dilution). All chickens inoculated with the 10 ؊2 to 10 ؊4 dilutions of the infectious stock and one of the two chickens inoculated with the 10 ؊5 dilution, but neither of the chickens inoculated with the 10 ؊6 dilution, became seropositive for anti-avian HEV antibody at 4 weeks postinoculation (wpi). Two serologically negative contact control chickens housed together with chickens inoculated with the 10 ؊2 dilution also seroconverted at 8 wpi. Viremia and shedding of virus in feces were variable in chickens inoculated with the 10 ؊2 to 10 ؊5 dilutions but were not detectable in those inoculated with the 10 ؊6 dilution. The infectivity titer of the infectious avian HEV stock was determined to be 5 ؋ 10 5 50% chicken infectious doses (CID 50 ) per ml. Eight 1-week-old turkeys were intravenously inoculated with 10 5 CID 50 of avian HEV, and another group of nine turkeys were not inoculated and were used as controls. The inoculated turkeys seroconverted at 4 to 8 wpi. In the inoculated turkeys, viremia was detected at 2 to 6 wpi and shedding of virus in feces was detected at 4 to 7 wpi. A serologically negative contact control turkey housed together with the inoculated ones also became infected through direct contact. This is the first demonstration of cross-species infection by avian HEV.Hepatitis E virus (HEV), the causative agent of hepatitis E, is an important human pathogen (1-2, 23-24, 26, 34-35). HEV is a positive-sense, single-stranded, nonenveloped RNA virus. The genome of HEV is about 7.2 kb and contains three open reading frames (ORFs) (23)(24)26). Hepatitis E is primarily transmitted through the fecal-oral route, with an incubation period of about 15 to 60 days. The mortality rate is generally low (about 1%); however, it can reach up to 15 to 25% among infected pregnant women (7,23,24

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“…Cynomolgus monkeys infected by intravenous inoculation of HEV provoked an increase in ALT, elevation of anti-HEV IgG, and slight lymphatic infiltration or necrotic change in the liver, although obvious clinical symptoms were not observed [1,20]. Furthermore, cynomolgus monkeys infected with HEV by the oral route did not show any clinical and hematological changes associated with acute hepatitis or HEV infection [12].…”

Section: Discussionmentioning

confidence: 95%

Epidemiology of Hepatitis E Virus in Indoor-Captive Cynomolgus Monkey Colony

Nakamura

Tsuchiya

Okahara

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. A serological survey of hepatitis E virus (HEV) antibody was conducted using 202 adult captive cynomolgus monkeys, who did not show any clinical signs of acute hepatitis. Out of these, 44 monkeys were sero-positive for anti-HEV IgG and all monkeys were negative for anti-HEV IgM. All positive monkeys came from either Vietnam or China, but none from the Philippines, Indonesia, or our facility. Selected 12 monkeys out of positive monkeys from Vietnum, including 9 positive and 3 negative, revealed mostly within the reference ranges for alanine aminotransferase (ALT) and asparatate aminotransferase (AST) by serum biochemistries. Their titers of anti-HEV IgG did not correlate with the concentrations of ALT and AST. Moreover, HEV-RNA could not be detected from any fecal specimens of the 12 monkeys. Thus, monkeys with anti-HEV IgG sero-positive did not seem to be source of the HEV-pollution, because 1) sero-positive monkeys did not excrete HEV-RNA from their feces, and 2) monkeys from the Philippines and Indonesia have remained to be sero-negative for anti-HEV IgG, even if the monkeys were kept in same animal room of our facility. From these results, it could be inferred that primary infection of HEV occurred in the exported countries, but not in our colony. The contamination of HEV in indoor-captive monkeys could be prevented by precise quarantine tests, including ELISA for detecting anti-HEV and RT-PCR for HEV RNA.

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Infectivity titration of a prototype strain of hepatitis E virus in cynomolgus monkeys

Cited by 128 publications

References 25 publications

Recombinant hepatitis E virus genomes infectious for primates: Importance of capping and discovery of a cis-reactive element

Recombinant hepatitis E virus genomes infectious for primates: Importance of capping and discovery of a cis-reactive element

Generation and Infectivity Titration of an Infectious Stock of Avian Hepatitis E Virus (HEV) in Chickens and Cross-Species Infection of Turkeys with Avian HEV

Epidemiology of Hepatitis E Virus in Indoor-Captive Cynomolgus Monkey Colony

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