Insertions and deletions in the hypervariable region of the hepatitis E virus genome in individuals with acute and chronic infection

Biedermann, Paula; Klink, Patrycja; Nocke, Maximilian K.; Papp, Christian-Patrick; Harms, Dominik; Kebelmann, Marianne; Thürmer, Andrea; Choi, Mira; Altmann, Britta; Todt, Daniel; Hofmann, Jörg; Bock, C.‐Thomas

doi:10.1111/liv.15517

Cited by 3 publications

(1 citation statement)

References 46 publications

(137 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The hypervariable region (HVR) within HEV’s first open reading frame is known to integrate sequence snippets of human and viral origin. Some insertions are associated with replication fitness in vitro and chronicity in vivo [ 79 , 80 , 81 , 82 ]. The off-label drug ribavirin is commonly used to treat chronically infected patients, but presents a high rate of treatment failures [ 83 ].…”

Section: Scientific Programmentioning

confidence: 99%

The International Virus Bioinformatics Meeting 2023

Hufsky,

Abecasis,

Babaian

et al. 2023

Viruses

View full text Add to dashboard Cite

The 2023 International Virus Bioinformatics Meeting was held in Valencia, Spain, from 24–26 May 2023, attracting approximately 180 participants worldwide. The primary objective of the conference was to establish a dynamic scientific environment conducive to discussion, collaboration, and the generation of novel research ideas. As the first in-person event following the SARS-CoV-2 pandemic, the meeting facilitated highly interactive exchanges among attendees. It served as a pivotal gathering for gaining insights into the current status of virus bioinformatics research and engaging with leading researchers and emerging scientists. The event comprised eight invited talks, 19 contributed talks, and 74 poster presentations across eleven sessions spanning three days. Topics covered included machine learning, bacteriophages, virus discovery, virus classification, virus visualization, viral infection, viromics, molecular epidemiology, phylodynamic analysis, RNA viruses, viral sequence analysis, viral surveillance, and metagenomics. This report provides rewritten abstracts of the presentations, a summary of the key research findings, and highlights shared during the meeting.

show abstract

Section: Scientific Programmentioning

confidence: 99%

The International Virus Bioinformatics Meeting 2023

Hufsky,

Abecasis,

Babaian

et al. 2023

Viruses

View full text Add to dashboard Cite

show abstract

Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Wißing,

Meister,

Nocke

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.

show abstract

Characterization of virus‒host recombinant variants of the hepatitis E virus

Paronetto,

Allioux,

Diméglio

et al. 2024

J Virol

View full text Add to dashboard Cite

Hepatitis E virus is a single-strand, positive-sense RNA virus that can lead to chronic infection in immunocompromised patients. Virus–host recombinant variants (VHRVs) have been described in such patients. These variants integrate part of human genes into the polyproline-rich region that could introduce new post-translational modifications (PTMs), such as ubiquitination. The aim of this study was to characterize the replication capacity of different VHRVs, namely, RNF19A, ZNF787, KIF1B, EEF1A1, RNA18, RPS17, and RPL6. We used a plasmid encoding the Kernow strain, in which the fragment encoding the S17 insertion was deleted (Kernow p6 delS17) or replaced by fragments encoding the different insertions. The HEV RNA concentrations in the supernatants and the HepG2/C3A cell lysates were determined via RT-qPCR. The capsid protein ORF2 was immunostained. The effect of ribavirin was also assessed. The HEV RNA concentrations in the supernatants and the cell lysates were higher for the variants harboring the RNF19A, ZNF787, KIF1B, RPS17, and EEF1A1 insertions than for the Kernow p6 del S17, while it was not with RNA18 or RPL6 fragments. The number of ORF2 foci was higher for RNF19A, ZNF787, KIF1B, and RPS17 than for Kernow p6 del S17. VHRVs with replicative advantages were less sensitive to the antiviral effect of ribavirin. No difference in PTMs was found between VHRVs with a replicative advantage and those without. In conclusion, our study showed that insertions did not systematically confer a replicative advantage in vitro . Further studies are needed to determine the mechanisms underlying the differences in replicative capacity. IMPORTANCE Hepatitis E virus (HEV) is a major cause of viral hepatitis. HEV can lead to chronic infection in immunocompromised patients. Ribavirin treatment is currently used to treat such chronic infections. Recently, seven virus–host recombinant viruses were characterized in immunocompromised patients. These viruses have incorporated a portion of a human gene fragment into their genome. We studied the consequences of these insertions on the replication capacity. We found that these inserted fragments could enhance virus replication for five of the seven recombinant variants. We also showed that the recombinant variants with replicative advantages were less sensitive to ribavirin in vitro . Finally, we found that the mechanisms leading to such a replicative advantage do not seem to rely on the post-translational modifications introduced by the human gene fragment that could have modified the function of the viral protein. The mechanisms involved in improving the replication of such recombinant viruses remain to be explored.

show abstract

Insertions and deletions in the hypervariable region of the hepatitis E virus genome in individuals with acute and chronic infection

Cited by 3 publications

References 46 publications

The International Virus Bioinformatics Meeting 2023

The International Virus Bioinformatics Meeting 2023

Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Characterization of virus‒host recombinant variants of the hepatitis E virus

Contact Info

Product

Resources

About