Ausencia de expresión de la proteína Core del virus de la hepatitis C en células dendríticas derivadas de monocitos humanos utilizando virus del Bosque de Semliki recombinante / Lack of expression of hepatitis c virus core protein in human monocyte-derived dendritic cells using recombinant semliki forest virus

ABSTRACT Hepatitis C Virus belongs to the Flaviviridae family. One proposed mechanism of HCV persistence in the ability to infect hematopoietic cells, including Dendritic cells (DCs). HCV infection of DCs could impair their functions that represent one of the mechanisms, thus hampering viral clearance by the host immune system. Among HCV-encoded proteins, the highly conserved Core protein has been suggested to be responsible for the immunomodulatory properties of this Hepacivirus. Recombinant viral vectors expressing the HCV Core protein and allowing its transduction and therefore the expression of the protein into DCs could be useful tools for the analysis of the properties of the Core protein. Vaccinia Virus and retrovirus have been used to transduce human DCs. Likewise, gene transfer into DCs using Semliki Forest Virus has been reported. This study aimed to express the HCV Core protein in human monocyte-derived DCs using an SFV vector, in which the subgenomic RNA encoding the structural proteins was replaced by the HCV Core sequence and then analyze the effects of its expression on DCs functions.

RESUMEN El virus de la Hepatitis C (VHC) pertenece a la familia Flaviviridae. Uno de los mecanismos propuestos de la persistencia del VHC es la capacidad de infectar células hematopoyéticas, incluidas las células dendríticas (DCs). La infección por VHC de DCs podría alterar sus funciones y corresponde a uno de los mecanismos que impiden el aclaramiento de la infección por VHC por el sistema inmunitario del hospedero. Entre las proteínas codificadas por el VHC, se ha sugerido que la proteína Core, altamente conservada, es responsable de las propiedades inmunomoduladoras de este Hepacivirus. Los vectores virales recombinantes que expresan la proteína Core y permiten su transducción a DCs podrían ser herramientas útiles para el análisis de las propiedades de esta proteína. El virus Vaccinia y el retrovirus se han utilizado para la transducción de DCs humanas. Del mismo modo, la transducción de DCs usando el virus del bosque de Semliki ha sido reportada. El objetivo de este estudio fue expresar la proteína Core de VHC en DCs derivadas de monocitos humanos utilizando un vector de SFV, en el que el ARN subgenómico que codifica las proteínas estructurales fue reemplazado por la secuencia Core del VHC y evaluar los efectos de su expresión en las funciones de DCs.

Neutralizing Antibody-Mediated Response and Risk of BK Virus-Associated Nephropathy.

BK virus-associated nephropathy (BKVAN) causes renal allograft dysfunction. The current management of BKVAN relies on pre-emptive adaptation of immunosuppression according to viral load monitoring. However, this empiric strategy is not always successful. Therefore, pretransplant predictive markers are needed. In a prospective longitudinal study, we enrolled 168 kidney transplant recipients and 69 matched donors. To assess the value of BKV genotype-specific neutralizing antibody (NAb) titers as a predictive marker for BKV replication, we measured BKV DNA load and NAb titers at transplant and followed patients for 24 months. After transplant, 52 (31%) patients displayed BKV replication: 24 (46%) patients were viruric and 28 (54%) patients were viremic, including 13 with biopsy-confirmed BKVAN. At any time, patients with high NAb titers against the replicating strain had a lower risk of developing BKV viremia (hazard ratio [HR], 0.44; 95% confidence interval [95% CI], 0.26 to 0.73; P=0.002). Each log10 increase in NAb titer decreased the risk of developing viremia by 56%. Replicating strains were consistent with donor transmission in 95% of cases of early BKV replication. Genotype mismatch between recipients' neutralization profiles before transplant and their subsequently replicating strain significantly increased the risk of developing viremia (HR, 2.27; 95% CI, 1.06 to 4.88; P=0.04). A NAb titer against the donor's strain <4 log10 before transplant significantly associated with BKV replication after transplant (HR, 1.88; 95% CI, 1.06 to 3.45; P=0.03). BKV genotype-specific NAb titers may be a meaningful predictive marker that allows patient stratification by BKV disease risk before and after transplant.

Problem-based learning in laboratory medicine resident education: a satisfaction survey.

Theoretical knowledge in biology and medicine plays a substantial role in laboratory medicine resident education. In this study, we assessed the contribution of problem-based learning (PBL) to improve the training of laboratory medicine residents during their internship in the department of virology, Strasbourg University Hospital, France. We compared the residents' satisfaction regarding an educational program based on PBL and a program based on lectures and presentations. PBL induced a high level of satisfaction (100%) among residents compared to lectures and presentations (53%). The main advantages of this technique were to create a situational interest regarding virological problems, to boost the residents' motivation and to help them identify the most relevant learning objectives in virology. However, it appears pertinent to educate the residents in appropriate bibliographic research techniques prior to PBL use and to monitor their learning by regular formative assessment sessions.

Natural non-homologous recombination led to the emergence of a duplicated V3-NS5A region in HCV-1b strains associated with hepatocellular carcinoma.

BACKGROUND: The emergence of new strains in RNA viruses is mainly due to mutations or intra and inter-genotype homologous recombination. Non-homologous recombinations may be deleterious and are rarely detected. In previous studies, we identified HCV-1b strains bearing two tandemly repeated V3 regions in the NS5A gene without ORF disruption. This polymorphism may be associated with an unfavorable course of liver disease and possibly involved in liver carcinogenesis. Here we aimed at characterizing the origin of these mutant strains and identifying the evolutionary mechanism on which the V3 duplication relies. METHODS: Direct sequencing of the entire NS5A and E1 genes was performed on 27 mutant strains. Quasispecies analyses in consecutive samples were also performed by cloning and sequencing the NS5A gene for all mutant and wild strains. We analyzed the mutant and wild-type sequence polymorphisms using Bayesian methods to infer the evolutionary history of and the molecular mechanism leading to the duplication-like event. RESULTS: Quasispecies were entirely composed of exclusively mutant or wild-type strains respectively. Mutant quasispecies were found to have been present since contamination and had persisted for at least 10 years. This V3 duplication-like event appears to have resulted from non-homologous recombination between HCV-1b wild-type strains around 100 years ago. The association between increased liver disease severity and these HCV-1b mutants may explain their persistence in chronically infected patients. CONCLUSIONS: These results emphasize the possible consequences of non-homologous recombination in the emergence and severity of new viral diseases.

45 years after the discovery of human polyomaviruses BK and JC: Time to speed up the understanding of associated diseases and treatment approaches.

Nearly 45 years after the discovery of the first two human polyomaviruses BK and JC, their life-long persistence and mechanisms of pathogenesis remain poorly understood and efficient antiviral treatments are severely lacking. In this review, we sought to provide an update on recent advances in understanding the life cycle of these two viruses, particularly focusing on their interaction with the host immune system and pathogenesis. We have also discussed novel treatment approaches and highlighted areas of future research.

Long-term storage and safe retrieval of human papillomavirus DNA using FTA elute cards.

Biobanking or collection and storage of specimens for future research purposes have become an essential tool in many fields of biomedical research and aims to provide a better understanding of disease mechanisms as well as the identification of disease-specific biomarkers that can navigate in complex diseases. In this study, we assessed the use of Flinders Technology Associates (FTA) cards as a long-term storage device for cervical specimens with suspected human papillomavirus (HPV) infections. HPV detection and genotyping results in liquid-based transport media were compared to HPV results from FTA cards. The overall agreement for the presence of any HPV infection between liquid-based medium and FTA cards stored for 1 year at ambient temperature was 100%. Reproducibility analysis of HPV detection and genotyping from FTA cards demonstrated that FTA cards are a reliable medium to store and preserve viral nucleic acids. Biobanking of cervical cells on FTA cards may provide a key resource for epidemiological and retrospective HPV studies.

Sequence Variation in Amplification Target Genes and Standards Influences Interlaboratory Comparison of BK Virus DNA Load Measurement.

International guidelines define a BK virus (BKV) load of ≥4 log10 copies/ml as presumptive of BKV-associated nephropathy (BKVN) and a cutoff for therapeutic intervention. To investigate whether BKV DNA loads (BKVL) are comparable between laboratories, 2 panels of 15 and 8 clinical specimens (urine, whole blood, and plasma) harboring different BKV genotypes were distributed to 20 and 27 French hospital centers in 2013 and 2014, respectively. Although 68% of the reported results fell within the acceptable range of the expected result ±0.5 log10, the interlaboratory variation ranged from 1.32 to 5.55 log10. Polymorphisms specific to BKV genotypes II and IV, namely, the number and position of mutations in amplification target genes and/or deletion in standards, arose as major sources of interlaboratory disagreements. The diversity of DNA purification methods also contributed to the interlaboratory variability, in particular for urine samples. Our data strongly suggest that (i) commercial external quality controls for BKVL assessment should include all major BKV genotypes to allow a correct evaluation of BKV assays, and (ii) the BKV sequence of commercial standards should be provided to users to verify the absence of mismatches with the primers and probes of their BKV assays. Finally, the optimization of primer and probe design and standardization of DNA extraction methods may substantially decrease interlaboratory variability and allow interinstitutional studies to define a universal cutoff for presumptive BKVN and, ultimately, ensure adequate patient care.

Influenza prevention in nursing homes: Great significance of seasonal variability and spatio-temporal pattern.

OBJECTIVE: This work evaluated seasonal variations and spatio-temporal pattern of respiratory tract infections (RTI) in geriatric nursing homes in order to improve effective surveillance, prevention, control and management of RTI. METHODS: Prospective surveillance of RTI (Low Respiratory Tract infections and Influenza Like Illnesses) was conducted in 11 sites in Alsace over a 10-year period with clinical case definitions and rapid tests (Immunoassay) to identify influenza virus. RESULTS: Influenza national epidemic was a period at high risk of RTI in nursing homes with variable impacts depending on the seasonal period. 2004-2005, 2008-2009, 2011-2012 and 2012-2013 were the periods with the highest impacts. The higher risk was not well understood during these four influenza epidemics and outbreaks occurred in numerous nursing homes despite the alerts and surveillance. CONCLUSION: Information about seasonal variability and spatio-temporal patterns of the RTI during the national epidemic periods is essential for the nursing homes in order to help the health care workers and the visitors to understand the risk for the residents and then to improve the implementation of the control and prevention measures.

Ten influenza seasons in France: distribution and timing of influenza A and B circulation, 2003-2013.

BACKGROUND: Describing the circulation of influenza viruses and the characteristics of seasonal epidemics remains an essential tool to optimize the strategies of influenza prevention and control. Special attention has been recently paid to influenza B in the context of the availability of a quadrivalent vaccine, containing two influenza B strains. METHODS: We used data from a practitioners-based influenza surveillance network to describe the circulation of influenza viruses in France from 2003-2004 to 2012-2013. Nasopharyngeal swabs taken from acute respiratory infection (ARI) patients between October and April were tested for influenza. We reported the number of influenza cases by virus type (A, B), subtype (A(H1), A(H3)) and B lineage (Yamagata, Victoria) in each season and determined the frequency of influenza B vaccine mismatch. We estimated weekly incidence of influenza by extrapolating reported influenza cases to the French population. We compared the temporal characteristics of the epidemics caused by influenza A(H1), A(H3) and B. RESULTS: Overall, 49,919 ARI patients were tested, of which 16,287 (32.6 %) were positive for influenza. Type B virus caused 23.7 % of all influenza cases. Virus subtypes A(H1) and A(H3) caused 51.6 % and 48.4 % of influenza A cases, respectively. Viruses of the B-Yamagata and B-Victoria lineage caused 62.8 % and 37.2 % of influenza B cases, respectively. There was an influenza B vaccine mismatch in three of the five seasons where influenza B caused 10 % or more of all influenza cases. Influenza A(H3) had the highest average value of estimated weekly incidence during the study period. Influenza B peaked an average 3.8 weeks later than influenza A when both virus types were circulating. No differences in the duration of influenza A and B epidemics were observed. CONCLUSIONS: Influenza A(H3) was the most prevalent influenza type during the study period. Influenza B caused around one fourth of all influenza cases and tended to circulate later than influenza A. The frequency of influenza B vaccine mismatches was substantial. Timely data on the circulation of influenza viruses collected within influenza surveillance systems are essential to optimize influenza prevention and control strategies.

[Clinical laboratory medicine: continuous amelioration with a book of objectives and satisfaction survey]. / Amélioration continue du DES de biologie médicale à l'aide d'un carnet de stage et d'un questionnaire d'évaluation de la satisfaction.

We report in this publication the use of two educational tools, a questionnaire of satisfaction and a training book, to improve the training of students during their internship in clinical laboratory at the "Pôle de biologie des Hôpitaux universitaires de Strasbourg" in France. First, the ongoing training was assessed by the interns with a questionnaire measuring satisfaction. The analysis of this questionnaire identified four key points to improve: 1) define the teaching objectives, 2) organize the training with a schedule, 3) revise certain teaching methods and 4) ensure better integration of the students in the team of medical biologists. After this assessment, we implemented a training book to answer these four points. Indeed, the training book presents the objectives, the schedule of training, and how to validate the educational objectives. A new assessment was performed again using the same methodology. Results showed an improvement in student satisfaction from 74 to 88 %. The questionnaire of satisfaction and the training book are presented in this article. The aim of the assessment of training combined with the training book is to incite the actors of the training (students and teachers) to continually improve the training. The objectives of the Pôle de Biologie are to obtain an 80 % satisfaction rate during the 6 months trainings and to reduce or eliminate dissatisfaction, and finally to ensure the validation by students of 80 to 100 % of their predetermined objectives.

Antiviral and Immunoregulatory Effects of Indoleamine-2,3-Dioxygenase in Hepatitis C Virus Infection.

In patients with hepatitis C virus (HCV) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (IDO) has been reported. IDO - a tryptophan-catabolizing enzyme - has been considered as both an innate defence mechanism and an important regulator of the immune response. The molecular mechanism of IDO induction in HCV infection and its role in the antiviral immune response remain unknown. Using primary human hepatocytes, we show that HCV infection stimulates IDO expression. IDO gene induction was transient and coincided with the expression of types I and III interferons (IFNs) and IFN-stimulated genes in HCV-infected hepatocytes. Overexpression of hepatic IDO prior to HCV infection markedly impaired HCV replication in hepatocytes, suggesting that IDO limits the spread of HCV within the liver. siRNA-mediated IDO knock-down revealed that IDO functions as an IFN-mediated anti-HCV effector. Hepatic IDO was most potently induced by IFN-x03B3;, and ongoing HCV replication could significantly upregulate IDO expression. IRF1 (IFN-regulatory factor 1) and STAT1 (signal transducer and activator of transcription 1) regulated hepatic IDO expression. Hepatic IDO expression also had a significant inhibitory effect on CD4+ T-cell proliferation. Our data suggest that hepatic IDO plays a dual role during HCV infection by slowing down viral replication and also regulating host immune responses.

Toward standardization of BK virus monitoring: evaluation of the BK virus R-gene kit for quantification of BK viral load in urine, whole-blood, and plasma specimens.

Screening of BK virus (BKV) replication is recommended to identify patients at increased risk of BKV-associated diseases. However, the heterogeneity of molecular techniques hinders the establishment of universal guidelines for BKV monitoring. Here we aimed to compare the performance of the CE-marked BK virus R-gene kit (R-gene) to the performance of our in-house assay for quantification of BKV DNA loads (BKVL). A 12-specimen panel from the Quality Control for Molecular Diagnostics (QCMD) organization, 163 urine samples, and 88 paired specimens of plasma and whole blood (WB) from transplant recipients were tested. Both the R-gene and in-house assays showed a good correlation within the QCMD panel (r = 0.995 and r = 0.989, respectively). BKVL were highly correlated between assays, although positive biases were observed with the in-house assay in analysis of urine (0.72 ± 0.83 log10 copies/ml), plasma (1.17 ± 0.63 log10 copies/ml), and WB (1.28 ± 0.37 log10 copies/ml). Recalibration with a common calibrator significantly reduced the bias in comparisons between assays. In contrast, BKVL was underestimated with the in-house PCR in eight samples containing BKV genotype II, presenting point mutations at primer-annealing sites. Using the R-gene assay, plasma and WB specimens were found to be equally suitable for quantification of BKVL, as indicated by the high correlation coefficient (r = 0.965, P < 0.0001). In conclusion, the R-gene assay demonstrated reliable performance and higher accuracy than the in-house assay for quantification of BKVL in urine and blood specimens. Screening of BKV replication by a well-validated commercial kit may enable clinical laboratories to assess viral loads with greater reproducibility and precision.

Influenza outbreaks management in a French psychiatric hospital from 2004 to 2012.

OBJECTIVE: Influenza epidemics can have consequences in terms of morbidity and mortality for the patients. This work assesses influenza outbreaks in order to validate and optimize alert and control measures in a psychiatric hospital. METHOD: The prospective monitoring of influenza episodes was conducted for 8 years in 19 units of a mental health hospital. Rapid influenza diagnostic tests were used. The study of the episodes with confirmed influenza cases was carried out. RESULTS: Influenza monitoring and alert were essential with information and laboratory-confirmed cases. Influenza was common with a total of 20 episodes for the studied period. A maximum of 25% (5/20) of the units were affected in 2008-2009. Rapid influenza diagnostic tests allowed a quick identification with an average time of 1.5 days. Mainly, control measures limited the spread of the influenza virus in units with patient not at high risk of complications. On the other hand, antiviral curative treatment and chemoprophylaxis are essential in units with patients at high risk of complications. CONCLUSION: In a psychiatric hospital, influenza management has to take into account the exposed patient's risks for influenza complications and to adapt the strategy according to the risks identified.

Genotype 1 hepatitis C virus envelope features that determine antiviral response assessed through optimal covariance networks.

The poor response to the combined antiviral therapy of pegylated alfa-interferon and ribavarin for hepatitis C virus (HCV) infection may be linked to mutations in the viral envelope gene E1E2 (env), which can result in escape from the immune response and higher efficacy of viral entry. Mutations that result in failure of therapy most likely require compensatory mutations to achieve sufficient change in envelope structure and function. Compensatory mutations were investigated by determining positions in the E1E2 gene where amino acids (aa) covaried across groups of individuals. We assessed networks of covarying positions in E1E2 sequences that differentiated sustained virological response (SVR) from non-response (NR) in 43 genotype 1a (17 SVR), and 49 genotype 1b (25 SVR) chronically HCV-infected individuals. Binary integer programming over covariance networks was used to extract aa combinations that differed between response groups. Genotype 1a E1E2 sequences exhibited higher degrees of covariance and clustered into 3 main groups while 1b sequences exhibited no clustering. Between 5 and 9 aa pairs were required to separate SVR from NR in each genotype. aa in hypervariable region 1 were 6 times more likely than chance to occur in the optimal networks. The pair 531-626 (EI) appeared frequently in the optimal networks and was present in 6 of 9 NR in one of the 1a clusters. The most frequent pairs representing SVR were 431-481 (EE), 500-522 (QA) in 1a, and 407-434 (AQ) in 1b. Optimal networks based on covarying aa pairs in HCV envelope can indicate features that are associated with failure or success to antiviral therapy.

Hepatitis C virus vaccines--progress and perspectives.

Approximately 170 million individuals, representing 3% of the global population, are infected with hepatitis C virus (HCV). Whereas strategies for antiviral therapies have markedly improved resulting in clinical licensing of direct-acting antivirals, the development of vaccines has been hampered by the high genetic variability of the virus as well as by the lack of suitable animal models for proof-of-concept studies. Nevertheless, there are several promising vaccine candidates in preclinical and clinical development. After a brief summary of the molecular virology and immunology relevant to vaccine development, this review explains the model systems used for preclinical vaccine development, and highlights examples for most recently developed HCV vaccine candidates.

Hepatitis C virus envelope glycoprotein signatures are associated with treatment failure and modulation of viral entry and neutralization.

BACKGROUND: A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape. METHODS: We used a bioinformatics and functional approach to investigate whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with HCV genotype 1. RESULTS: Bioinformatics analysis identified 1 sustain virological response (R)-related residue in E1 (219T) and 2 non-SVR (NR)-related molecular signatures in E2 (431A and 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating NR patients from R patients. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pretreatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C). CONCLUSIONS: Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor use and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.

Neutralizing antibodies and pathogenesis of hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role in the resulting pathogenesis. Furthermore, viral evasion from host neutralizing antibodies has been revealed to be an important contributor in leading both to viral persistence in acute liver graft infection following liver transplantation, and to chronic viral infection. The development of novel model systems to study HCV entry and neutralization has allowed a detailed understanding of the molecular mechanisms of virus-host interactions during antibody-mediated neutralization. The understanding of these mechanisms will ultimately contribute to the development of novel antiviral preventive strategies for liver graft infection and an urgently needed vaccine. This review summarizes recent concepts of the role of neutralizing antibodies in viral clearance and protection, and highlights consequences of viral escape from neutralizing antibodies in the pathogenesis of HCV infection.

Challenges for HCV vaccine development in HIV-HCV coinfection.

It is estimated that 4-5 million HIV-infected patients are coinfected with HCV. The impact of HIV on the natural course of HCV infection is deleterious. This includes a higher rate of HCV persistence and a faster rate of fibrosis progression. Coinfected patients show poor treatment outcome following standard HCV therapy. Although direct antiviral agents offer new therapeutic options, their use is hindered by potential drug interactions and toxicity in HIV-infected patients under HAART. Overtime, a large reservoir of HCV genotype 1 patients will accumulate in resource poor countries where the hepatitis C treatment is not easily affordable and HIV therapy remains the primary health issue for coinfected individuals. HCV vaccines represent a promising strategy as an adjunct or alternative to current HCV therapy. Here, the authors review the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discuss the challenges for vaccine development in HIV-HCV coinfection.

Mutations that alter use of hepatitis C virus cell entry factors mediate escape from neutralizing antibodies.

BACKGROUND & AIMS: The development of vaccines and other strategies to prevent hepatitis C virus (HCV) infection is limited by rapid viral evasion. HCV entry is the first step of infection; this process involves several viral and host factors and is targeted by host-neutralizing responses. Although the roles of host factors in HCV entry have been well characterized, their involvement in evasion of immune responses is poorly understood. We used acute infection of liver graft as a model to investigate the molecular mechanisms of viral evasion. METHODS: We studied factors that contribute to evasion of host immune responses using patient-derived antibodies, HCV pseudoparticles, and cell culture-derived HCV that express viral envelopes from patients who have undergone liver transplantation. These viruses were used to infect hepatoma cell lines that express different levels of HCV entry factors. RESULTS: By using reverse genetic analyses, we identified altered use of host-cell entry factors as a mechanism by which HCV evades host immune responses. Mutations that alter use of the CD81 receptor also allowed the virus to escape neutralizing antibodies. Kinetic studies showed that these mutations affect virus-antibody interactions during postbinding steps of the HCV entry process. Functional studies with a large panel of patient-derived antibodies showed that this mechanism mediates viral escape, leading to persistent infection in general. CONCLUSIONS: We identified a mechanism by which HCV evades host immune responses, in which use of cell entry factors evolves with escape from neutralizing antibodies. These findings advance our understanding of the pathogenesis of HCV infection and might be used to develop antiviral strategies and vaccines.

Circulation of genotype 4 hepatitis E virus in Europe: first autochthonous hepatitis E infection in France.

BACKGROUND: Human HEV infections reported in Europe without previous travel to endemic regions are linked to exposure to genotype 3 Hepatitis E virus (HEV).Genotype 3 is widely distributed through human cases and zoonotic reservoir. The geographical distribution of genotype 4 is limited to Asian countries. OBJECTIVES: The first human case of autochthonous genotype 4 hepatitis E infection was reported in France. STUDY DESIGN: The HEV infection was described in an immunosuppressed patient, presenting an acute myeloblastic leukemia. Investigation of the case was performed on detection of HEV markers in the patient and in the environment. RESULTS: Hepatitis E infection was diagnosed on the basis of HEV RNA viremia, and detection of anti-HEV IgM. The prognostic of leukemia was favorable and HEV was cleared without relapsing. HEV isolate was classified into genotype 4. CONCLUSIONS: The recent characterization of genotype 4 HEV through swine surveillance in Europe and the description of the first human case in France open interesting questions about the circulation of this genotype: health risks in human population, transmission patterns, and zoonotic reservoir.