Resolution of hepatitis E virus infection in CD8+ T cell-depleted rhesus macaques

Bremer, William G.; Blasczyk, Heather; Yin, Xin; Salinas, Eduardo; Grakoui, Arash; Feng, Zongdi; Walker, Christopher M.

doi:10.1016/j.jhep.2021.04.036

Cited by 20 publications

(27 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study showed that depletion of CD8+ T cells in rhesus monkeys before HEV challenge only prolonged infection by 1 week and failed to cause chronicity, suggesting that the deficit in CD8+ T cell was compensated by other arms of the adaptive response, most likely neutralizing antibodies and/or CD4+ T cells that have antiviral effector function. [ 41 ] In our rabbit model instead, generalized immune suppression induced by immunosuppressants as in transplant patients with HEV chronic infection affects all arms of the adaptive response, which likely explains the successful establishment of HEV chronicity. Of note, host responses primarily related to the regulation of wound healing and extracellular matrix were active during HEV persistent infection.…”

Section: Discussionmentioning

confidence: 99%

Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies

Zhang

Shu

et al. 2022

Hepatology

Self Cite

View full text Add to dashboard Cite

Background and Aims HEV infection can lead to chronicity and rapid progression to liver fibrosis and cirrhosis in immunocompromised organ transplant recipients. Robust animal models are urgently needed to study the pathogenesis and test the efficacy of vaccines and antiviral drugs in immunosuppressed settings. Approach and Results Cyclosporin A was used to induce immunosuppression. Rabbits were challenged with genotype 3 or 4 HEV (i.e., the rabbit‐derived HEV3 and human‐derived HEV3 or HEV4). We assessed HEV markers within 13 weeks post inoculation (wpi) and pathological changes by hematoxylin and eosin and Masson staining at 4, 8, or 13 wpi. Chronic HEV infection was successfully established in immunocompromised rabbits. HEV RNA and/or antigens were detected in the liver, kidney, intestine, urine, and cerebrospinal fluid samples. Chronically infected animals exhibited typical characteristics of liver fibrosis development. Intrahepatic transcriptomic analysis indicated activation of both innate and adaptive immunity. Establishment of HEV chronicity likely contributed to the inhibited T‐cell immune response. Ribavirin is effective in clearing HEV infection in immunocompromised rabbits. Most interestingly, vaccination completed before immunosuppression conferred full protection against both HEV3 and HEV4 infections, but vaccination during immunosuppression was only partially protective, and the efficacy did not improve with increased or additional vaccine doses. Conclusions The immunocompromised rabbit model of both chronic HEV3 and HEV4 infection that was established captured the key features of chronic HEV infection in transplant patients, including liver fibrogenesis, and revealed the distinct effectiveness of vaccination administered before or under immunosuppression. This rabbit model is valuable for understanding the pathogenesis of chronic hepatitis E, as well as for evaluating antiviral agents and vaccines.

show abstract

Section: Discussionmentioning

confidence: 99%

Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies

Zhang

Shu

et al. 2022

Hepatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…These observations in the human setting are in agreement with recent data from the chicken as well as rhesus macaque HEV infection models that indicated an important role of HEV-specific CD8+ T cells in viral clearance. 3,4 The number of HEV-specific T-cell responses correlated negatively with viral load as well as ALT levels in chronic HEV infection (Fig. S4C,D).…”

Section: Discussionmentioning

confidence: 92%

“…Recent in vivo evidence from 2 animal models (chicken and rhesus macaque) demonstrates an important role of HEV-specific CD8+ T cells in HEV control. 3,4 However, in humans, there is still a paucity of data on HEV-specific CD8+ T-cell immunity. 5 Studies using recombinant HEV capsid protein (corresponding to open reading frame [ORF] 2) as well as overlapping peptides covering some or all HEV domains (ORF1-3) showed broad and vigorous HEV-specific CD8+ T-cell responses in immunocompetent patients with acute infection that contracted upon resolution of infection.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of CD8+ T-cell failure in chronic hepatitis E virus infection

Kemming

Gundlach

Panning

et al. 2022

Journal of Hepatology

View full text Add to dashboard Cite

“…At present, non-human primates, including swine, rabbits, mice and rats, usually served as experimental subjects in most HEV studies [ 15 – 17 ], but all these animal models have shortcomings [ 18 , 19 ] . By contrast, Bama miniature pigs are an ideal infection model used extensively in research, especially for long-term trials [ 20 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Researchers have had to use animals, such as non-human primates, swine, rabbits, mice and rats for most studies [ 15 – 17 ]. However, investigations based on rabbit, mouse and rat models have disadvantages when used to study clinical manifestations of HEV infection, while high costs, operational challenges and labor-intensive resource needs have limited the use of non-human primate and conventional swine models for such studies [ 18 , 19 ]. Bama miniature pigs have served as a genetically stable, highly inbred, easily handled and low cost viable infection model that are currently used extensively in research, especially in long-term trials [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Identification and pathogenicity of hepatitis E Virus from laboratory Bama miniature pigs

et al. 2022

View full text Add to dashboard Cite

Background Hepatitis E virus (HEV) genotypes 3 and 4 are zoonotic. In this study, HEV infection in laboratory Bama miniature pigs in Sichuan Province of China was investigated. Firstly, one hundred rectal swabs were collected for HEV RNA testing, and chose positive samples for sequence analysis. Concurrently, for pathogenicity study, six healthy Bama miniature pigs were randomly divided into two groups of 3 pigs each. A total of 500 μL of HEV stock (positive fecal samples identified in this study) was inoculated intravenously into each pig in the experimental group, and the three pigs in the other group served as negative controls. Serum and fecal samples were collected at 1 to 10 weeks post-inoculation (wpi) for alanine aminotransferase (ALT) levels, anti-HEV antibodies and HEV RNA detection, respectively. During necropsies, liver lesions and HEV antigen in liver were observed at 10 wpi. Results The rate of fecal sample HEV RNA-positivity was 12% (12/100). Sequence comparisons indicated that partial ORF1 and ORF2 gene sequences of this isolate shared highest identities with corresponding sequences of genotype 4a HEV isolates (81.4%-96.1% and 89.9%-97.1%, respectively). Phylogenetic tree analysis further demonstrated that sequences of this isolate clustered together with sub-genotype 4a HEV isolate sequences. Experimentally, the pathogenicity of Bama miniature pigs infected with this isolate exhibited viremia, fecal virus shedding, seroconversion, ALT level increasing, liver lesions and HEV antigen in liver. Conclusions This is the first study to confirm that HEV is currently circulating in laboratory Bama miniature pigs in China and this isolate can successfully infect Bama miniature pigs experimentally. More importantly, this study suggested HEV screening of laboratory pigs should be conducted to prevent research personnel from acquiring zoonotic HEV infections.

show abstract

Resolution of hepatitis E virus infection in CD8+ T cell-depleted rhesus macaques

Cited by 20 publications

References 33 publications

Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies

Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies

Mechanisms of CD8+ T-cell failure in chronic hepatitis E virus infection

Identification and pathogenicity of hepatitis E Virus from laboratory Bama miniature pigs

Contact Info

Product

Resources

About