Pathogénèse et adaptation du virus de l'hépatite E chez l'immunodéprimé

Les facteurs virologiques et immunologiques impliqués dans la persistance du virus de l'hépatite E (VHE) et dans la fibrose hépatique nécessitent d'être mieux caractérisés. L'hétérogénéité de la quasi-espèce virale au moment de la phase aiguë a été étudiée au niveau de la polyprotéine non structurale (ORF1) et de la protéine de capside (ORF2). Nos résultats ont montré qu'une plus grande hétérogénéité de la quasi-espèce à la phase aiguë était associée à la persistance du VHE. Chez les patients développant une infection chronique, une plus faible concentration sérique de cytokines inflammatoires, une plus faible activation des lymphocytes T et de fortes concentrations sériques en chimiokines ont été observées. Chez les patients chroniquement infectés, la plus faible diversification de la quasi-espèce lors de la première année d'infection était associée à la progression de la fibrose hépatique. Lors du suivi de l'évolution du génome du VHE chez un patient chroniquement infecté, peu de variations de la séquence consensus ont été observées mais une insertion de fragment de gène humain a été caractérisée. Cette découverte ouvre de nouvelles perspectives dans la compréhension de l'adaptation du VHE à son hôteIdentification of factors influencing HEV persistence and liver fibrosis is needed. The relationship between quasispecies heterogeneity and the outcome of the acute phase was studied in the non structural polyprotein (ORF1) and the capside protein (ORF2). We have shown that great quasispecies heterogeneity was associated with HEV persistence. In addition, weak inflammatory response, low T-cell activation and high serum concentrations of the chemokines implicated in leukocyte recruitment to the liver were also associated with HEV persistence. Patients with chronic infection and progressing liver fibrosis had less quasispecies diversification during the first year. Study of the genome evolution during a chronic infection has shown a limited number of mutations over time and a virus-host recombinant was foun

Key Role of Polyphosphoinositides in Dynamics of Fusogenic Nuclear Membrane Vesicles

The role of phosphoinositides has been thoroughly described in many signalling and membrane trafficking events but their function as modulators of membrane structure and dynamics in membrane fusion has not been investigated. We have reconstructed models that mimic the composition of nuclear envelope precursor membranes with naturally elevated amounts of phosphoinositides. These fusogenic membranes (membrane vesicle 1(MV1) and nuclear envelope remnants (NER) are critical for the assembly of the nuclear envelope. Phospholipids, cholesterol, and polyphosphoinositides, with polyunsaturated fatty acid chains that were identified in the natural nuclear membranes by lipid mass spectrometry, have been used to reconstruct complex model membranes mimicking nuclear envelope precursor membranes. Structural and dynamic events occurring in the membrane core and at the membrane surface were monitored by solid-state deuterium and phosphorus NMR. “MV1-like” (PC∶PI∶PIP∶PIP2, 30∶20∶18∶12, mol%) membranes that exhibited high levels of PtdIns, PtdInsP and PtdInsP2 had an unusually fluid membrane core (up to 20% increase, compared to membranes with low amounts of phosphoinositides to mimic the endoplasmic reticulum). “NER-like” (PC∶CH∶PI∶PIP∶PIP2, 28∶42∶16∶7∶7, mol%) membranes containing high amounts of both cholesterol and phosphoinositides exhibited liquid-ordered phase properties, but with markedly lower rigidity (10–15% decrease). Phosphoinositides are the first lipids reported to counterbalance the ordering effect of cholesterol. At the membrane surface, phosphoinositides control the orientation dynamics of other lipids in the model membranes, while remaining unchanged themselves. This is an important finding as it provides unprecedented mechanistic insight into the role of phosphoinositides in membrane dynamics. Biological implications of our findings and a model describing the roles of fusogenic membrane vesicles are proposed

Development of a World Health Organization International Reference Panel for different genotypes of hepatitis E virus for nucleic acid amplification testing.

Globally, hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Epidemiology and clinical presentation of hepatitis E vary greatly by location and are affected by the HEV genotype. Nucleic acid amplification technique (NAT)-based assays are important for the detection of acute HEV infection as well for monitoring chronic cases of hepatitis E. The aim of the study was to evaluate a panel of samples containing different genotypes of HEV for use in nucleic NAT-based assays. The panel of samples comprises eleven different members including HEV genotype 1a (2 strains), 1e, 2a, 3b, 3c, 3e, 3f, 4c, 4g as well as a human isolate related to rabbit HEV. Each laboratory assayed the panel members directly against the 1 World Health Organization (WHO) International Standard (IS) for HEV RNA (6329/10) which is based upon a genotype 3 a strain. The samples for evaluation were distributed to 24 laboratories from 14 different countries and assayed on three separate days. Of these, 23 participating laboratories returned a total of 32 sets of data; 17 from quantitative assays and 15 from qualitative assays. The assays used consisted of a mixture of in-house developed and commercially available assays. The results showed that all samples were detected consistently by the majority of participants, although in some cases, some samples were detected less efficiently. Based on the results of the collaborative study the panel (code number 8578/13) was established as the "1st International Reference Panel (IRP) for all HEV genotypes for NAT-based assays" by the WHO Expert Committee on Biological Standardization. This IRP will be important for assay validation and ensuring adequate detection of different genotypes and clinically important sub-genotypes of HEV

Prediction of SARS-CoV-2 Variant Lineages Using the S1-Encoding Region Sequence Obtained by PacBio Single-Molecule Real-Time Sequencing

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the causal agent of the COVID-19 pandemic that emerged in late 2019. The outbreak of variants with mutations in the region encoding the spike protein S1 sub-unit that can make them more resistant to neutralizing or monoclonal antibodies is the main point of the current monitoring. This study examines the feasibility of predicting the variant lineage and monitoring the appearance of reported mutations by sequencing only the region encoding the S1 domain by Pacific Bioscience Single Molecule Real-Time sequencing (PacBio SMRT). Using the PacBio SMRT system, we successfully sequenced 186 of the 200 samples previously sequenced with the Illumina COVIDSeq (whole genome) system. PacBio SMRT detected mutations in the S1 domain that were missed by the COVIDseq system in 27/186 samples (14.5%), due to amplification failure. These missing positions included mutations that are decisive for lineage assignation, such as G142D (n = 11), N501Y (n = 6), or E484K (n = 2). The lineage of 172/186 (92.5%) samples was accurately determined by analyzing the region encoding the S1 domain with a pipeline that uses key positions in S1. Thus, the PacBio SMRT protocol is appropriate for determining virus lineages and detecting key mutations

Special Issue “Recent Progress in Hepatitis A Virus Research”

The hepatitis A virus (HAV) is still one of the leading causes of acute viral hepatitis worldwide, despite there being an anti-HAV vaccine [...

Pathogénèse et adaptation du virus de l'hépatite E chez l'immunodéprimé

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Hepatitis A: Epidemiology, High-Risk Groups, Prevention and Research on Antiviral Treatment

International audienceThe hepatitis A virus (HAV) is a leading cause of acute viral hepatitis worldwide. It is transmitted mainly by direct contact with patients who have been infected or by ingesting contaminated water or food. The virus is endemic in low-income countries where sanitary and sociodemographic conditions are poor. Paradoxically, improving sanitary conditions in these countries, which reduces the incidence of HAV infections, can lead to more severe disease in susceptible adults. The populations of developed countries are highly susceptible to HAV, and large outbreaks can occur when the virus is spread by globalization and by increased travel and movement of foodstuffs. Most of these outbreaks occur among high-risk groups: travellers, men who have sex with men, people who use substances, and people facing homelessness. Hepatitis A infections can be prevented by vaccination; safe and effective vaccines have been available for decades. Several countries have successfully introduced universal mass vaccination for children, but high-risk groups in high-income countries remain insufficiently protected. The development of HAV antivirals may be important to control HAV outbreaks in developed countries where a universal vaccination programme is not recommended

Réplication du virus de l’hépatite E dans les cellules intestinales: Une nouvelle facette de ce virus dévoilée

International audienc