title: Characterization of the polyproline region of the hepatitis E virus in immunocompromised patients.
abstract: 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-α-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.
authors.affiliation: INSERM, UMR1043, Toulouse, France Department of Virology, CHU Purpan, Toulouse, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lhomme
authors.affiliation: INSERM, UMR1043, Toulouse, France Department of Virology, CHU Purpan, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Abravanel
authors.affiliation: INSERM, UMR1043, Toulouse, France Department of Virology, CHU Purpan, Toulouse, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Dubois
authors.affiliation: INSERM, UMR1043, Toulouse, France Department of Virology, CHU Purpan, Toulouse, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Sandres-Saune
authors.affiliation: Department of Virology, CHU Purpan, Toulouse, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Mansuy
authors.affiliation: INSERM, UMR1043, Toulouse, France Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.affiliation: INSERM, UMR1043, Toulouse, France Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.affiliation: INSERM, UMR1043, Toulouse, France Department of Virology, CHU Purpan, Toulouse, France izopet.j@chu-toulouse.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Izopet
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D016679:Genome, Viral; D016752:Hepatitis E virus / Q000737:chemistry* / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D016867:Immunocompromised Host; D008969:Molecular Sequence Data; D016377:Organ Transplantation; D010455:Peptides / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D010455:Peptides; C011083:polyproline
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