Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection

Suneetha, Pothakamuri Venkata; Pischke, Sven; Schlaphoff, V.; Grabowski, Jan; Fytili, P.; Gronert, A; Bremer, Birgit; Markova, Antoaneta; Jaroszewicz, Jerzy; Bara, Christoph; Manns, Michael P.; Cornberg, Markus; Wedemeyer, Heiner

doi:10.1002/hep.24738

Cited by 164 publications

(185 citation statements)

References 48 publications

(70 reference statements)

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“…The M domain contains T cell epitopes (1). Thus, the immune pressure mediated by T cells could explain the difference in selection, since the T cell response determines HEV eradication (33). An effective immune response should lead to less conservation of amino acid sequences, which is in line with our observations.…”

Section: Discussionsupporting

confidence: 88%

“…Since the virus is not cytolytic, the elimination of infected hepatocytes may depend on the degree of T cell activation. Patients who cleared their HEV infection after transplantation have been found to have a strong, HEV-specific T cell response (33). We found that the serum concentrations of five chemokines were higher in those patients whose HEV infection became chronic.…”

Section: Discussionmentioning

confidence: 65%

“…But little is known about the immune response and cytokine secretion in immunocompromised patients. However, it was shown recently that recovery from an HEV infection depends on the responses of multispecific T cells to HEV and the secretion of gamma interferon (IFN-␥) (33).…”

mentioning

confidence: 99%

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Hepatitis E Virus Quasispecies and the Outcome of Acute Hepatitis E in Solid-Organ Transplant Patients

Lhomme

Abravanel

Dubois

et al. 2012

J Virol

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c Hepatitis E virus (HEV) infections are responsible for chronic hepatitis in immunocompromised patients, and this can evolve to cirrhosis. Like all RNA viruses, HEV exists as a mixture of heterogeneous viruses defining quasispecies. The relationship between the genetic heterogeneity described as a quasispecies, cytokine secretion, and the outcome of acute hepatitis in immunocompromised patients remains to be elucidated. We cloned and sequenced the region encoding the M and P capsid domains of HEV from eight solid-organ transplant (SOT) patients with acute HEV infection who subsequently cleared the virus and from eight SOT patients whose infection became chronic. We analyzed the cytokines and chemokines in the sera of these SOT patients by multianalyte profiling. The nucleotide sequence entropy and genetic distances were greater in patients whose infections became chronic. A lower K a /K s ratio was associated with the persistence of HEV. The patients who developed chronic infection had lower serum concentrations of interleukin-1 (IL-1) receptor antagonist and soluble IL-2 receptor. Increased concentrations of the chemokines implicated in leukocyte recruitment to the liver were associated with persistent infection. Those patients with chronic HEV infection and progressing liver fibrosis had less quasispecies diversification during the first year than patients without liver fibrosis progression. Great quasispecies heterogeneity, a weak inflammatory response, and high serum concentrations of the chemokines involved in leukocyte recruitment to the liver in the acute phase were associated with persistent HEV infection. Slow quasispecies diversification during the first year was associated with rapidly developing liver fibrosis.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 65%

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Hepatitis E Virus Quasispecies and the Outcome of Acute Hepatitis E in Solid-Organ Transplant Patients

Lhomme

Abravanel

Dubois

et al. 2012

J Virol

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“…10 It is known to be non-enveloped in bile and faeces, and is present in blood, coated in a lipid membrane. HEV consists of a 5' short noncoding region (NCR), ORF1 (which encodes the nonstructural proteins), ORF3 (which encodes a small multifunctional protein), ORF2…”

Section: The Molecular Biology Of Hepatitis E Virusmentioning

confidence: 99%

Review article: hepatitis E—a concise review of virology, epidemiology, clinical presentation and therapy

Donnelly

Scobie

Crossan

et al. 2017

Aliment Pharmacol Ther

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SummaryBackground: Hepatitis E virus (HEV) is a leading cause of acute icteric hepatitis and acute liver failure in the developing world. During the last decade, there has been increasing recognition of autochthonous (locally acquired) HEV infection in developed countries. Chronic HEV infection is now recognised, and in transplant recipients this may lead to cirrhosis and organ failure.Aim: To detail current understanding of the molecular biology of HEV, diagnostic and therapeutic strategies and propose future directions for basic science and clinical research.Methods: PubMed was searched for English language articles using the key words "hepatitis E", "viral hepatitis", "autochthonous infection", "antiviral therapy", "liver transplantation", "acute", "chronic", "HEV", "genotype", "transmission" "food-borne", "transfusion". Additional relevant publications were identified from article reference lists. Future work should focus on increasing awareness of HEV infection in the developed world, emphasising the need for clinicians to have a low threshold for HEV testing, particularly in immunosuppressed patients. Patients at potential risk of chronic HEV infection must also be educated and given advice regarding prevention of infection.

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“…The development of a chronic HEV infection also seems to be associated with a weak inflammatory response, poor Tcell activation, and high serum concentrations of the chemokines involved in leukocyte recruitment to the liver (7). Another study reported that the evolution to chronic infection is associated with an impaired specific T-cell response (9).…”

mentioning

confidence: 99%

Characterization of the Polyproline Region of the Hepatitis E Virus in Immunocompromised Patients

Lhomme

Abravanel

Dubois

et al. 2014

J Virol

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Little is known about virus adaptation in immunocompromised patients with chronic genotype 3 hepatitis E virus (HEV3) infections. Virus-host recombinant strains have been isolated recently from chronically infected patients. The nature and incidence of such recombinant events occurring during infections of solid-organ transplant (SOT) recipients are essentially unknown. The polyproline region (PPR) of strains isolated from SOT patients was sequenced during the acute-infection phase (n ‫؍‬ 59) and during follow-up of patients whose infections became chronic (n ‫؍‬ 27). These 27 HEV strains included 3 (11%) that showed recombinant events 12, 34, 48, or 88 months after infection. In one strain, parts of the PPR and the RNA-dependent RNA polymerase were concomitantly inserted. In the second, a fragment of a human tyrosine aminotransferase (TAT) gene was inserted first, followed by a fragment of PPR. A fragment of the human inter-␣-trypsin inhibitor (ITI) gene was inserted in the third. All the inserted sequences were rich in aliphatic and basic amino acids. In vitro growth experiments suggest that the ITI insertion promoted more vigorous virus growth. In silico studies showed that the inserted sequences could provide potential acetylation, ubiquitination, and phosphorylation sites. We found that recombinant events had occurred in the HEV PPR in approximately 11% of the strains isolated from chronically infected transplant patients followed up in Toulouse University Hospital. These inserted fragments came from the HEV genome or a human gene and could enhance virus replication. IMPORTANCE Hepatitis E virus (HEV) can cause chronic infections in immunocompromised patients, including solid-organ transplant (SOT)recipients. Two strains that had undergone recombination with human ribosomal genes were described recently. The strains with inserted sequences replicated better in vitro. Little is known about the frequency of such recombinant events or how such an insertion enhances replication. We therefore investigated 59 SOT patients infected with HEV and found 3 strains with 4 recombinant events in 27 of these patients whose infection became chronic. The 4 inserted sequences were of different origins (human gene or HEV genome), but all were enriched in aliphatic and basic amino acids and provided potential regulation sites. Our data indicate that recombinant events occur in approximately 11% of strains isolated from chronically infected patients. The structures of the inserted sequences provide new clues as to how the inserted sequences could foster virus replication.

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Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection

Cited by 164 publications

References 48 publications

Hepatitis E Virus Quasispecies and the Outcome of Acute Hepatitis E in Solid-Organ Transplant Patients

Hepatitis E Virus Quasispecies and the Outcome of Acute Hepatitis E in Solid-Organ Transplant Patients

Review article: hepatitis E—a concise review of virology, epidemiology, clinical presentation and therapy

Characterization of the Polyproline Region of the Hepatitis E Virus in Immunocompromised Patients

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