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Vaccine After several attempts to develop a vaccine against hepatitis E, in a successful phase II trial of a novel HEV vaccine was described [ ]. Conclusions and Recommendations The great majority of HEV infections take a self-limiting, asymptomatic clinical course. Funding This research received no external funding. Conflicts of Interest The authors declare no conflict of interest. References 1. Adlhoch C. Pischke S. Hepatitis e virus: Infection beyond the liver?

Hoofnagle J. Hepatitis e. Rein D. The global burden of hepatitis e virus genotypes 1 and 2 in Imagawa T. Evaluation of heating conditions for inactivation of hepatitis e virus genotypes 3 and 4. Food Prot. Wedemeyer H. Pathogenesis and treatment of hepatitis e virus infection. Terio V. Occurrence of hepatitis a and e and norovirus gi and gii in ready-to-eat vegetables in italy. Food Microbiol. Maunula L. Tracing enteric viruses in the european berry fruit supply chain. Oeser C. Epidemiology of hepatitis e in england and wales: A year retrospective surveillance study, — Hunter J.

Coastal clustering of hev; Cornwall, UK. Purpari G. Molecular characterization of human enteric viruses in food, water samples, and surface swabs in sicily. First report of the presence of hepatitis e virus in scottish-harvested shellfish purchased at retail level. Food Environ.

Romalde J. An overview of 20 years of studies on the prevalence of human enteric viruses in shellfish from galicia, spain. Blood-borne hepatitis e virus transmission: A relevant risk for immunosuppressed patients. Mallet V. Transmission of hepatitis e virus by plasma exchange: A case report. Mullhaupt B. Hepatitis e blood donor screening-more than a mere drop in the ocean? Horvatits T. Lack of evidence for human serum albumin as major source of hev infections. Westholter D. Hev-positive blood donations represent a relevant infection risk for immunosuppressed recipients.

Riveiro-Barciela M. Red blood cell transfusion-transmitted acute hepatitis e in an immunocompetent subject in europe: A case report. Thrombotic thrombocytopenic purpura relapse induced by acute hepatitis e transmitted by cryosupernatant plasma and successfully controlled with ribavirin. Woo P. New hepatitis e virus genotype in camels, the middle east. Smith D. Proposed reference sequences for hepatitis e virus subtypes. Murphy E. First detection of hepatitis e virus orthohepevirus c in wild brown rats rattus norvegicus from great britain.

Zoonoses Public Health. Sridhar S. Rat hepatitis e virus as cause of persistent hepatitis after liver transplant. Andonov A. Rat hepatitis e virus linked to severe acute hepatitis in an immunocompetent patient. Hartl J. Hepatitis e seroprevalence in europe: A meta-analysis.

Hepatitis e seroprevalence in the americas: A systematic review and meta-analysis. Liver Int. Helsen N. Stem cell-derived hepatocytes: A novel model for hepatitis e virus replication. Allweiss L. Human liver chimeric mice as a new model of chronic hepatitis e virus infection and preclinical drug evaluation. Sayed I. Study of hepatitis e virus infection of genotype 1 and 3 in mice with humanised liver. Suneetha P. Hepatitis e virus hev -specific t-cell responses are associated with control of hev infection.

Brown A. Characterization of the specificity, functionality, and durability of host t-cell responses against the full-length hepatitis e virus. Kamar N. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-e virus infection after organ transplantation. Pegylated interferon-alpha for treating chronic hepatitis e virus infection after liver transplantation.

Haagsma E. Treatment of chronic hepatitis e in liver transplant recipients with pegylated interferon alpha-2b. Liver Transpl. Ribavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection. Brief communication: Case reports of ribavirin treatment for chronic hepatitis e. Ribavirin treatment of acute and chronic hepatitis e: A single-centre experience.

Ribavirin for chronic hepatitis e virus infection in transplant recipients. Zhu F. Efficacy and safety of a recombinant hepatitis e vaccine in healthy adults: A large-scale, randomised, double-blind placebo-controlled, phase 3 trial. European Association for the Study of the Liver Easl clinical practice guidelines on hepatitis e virus infection.

Comparison of autochthonous and imported cases of hepatitis a or hepatitis e. Sebode M. New foe treated with old guns-supportive role of steroids in the treatment of acute severe hepatitis e. BMC Gastroenterol. Increased hev seroprevalence in patients with autoimmune hepatitis. Davern T. Acute hepatitis e infection accounts for some cases of suspected drug-induced liver injury.

Fontana R. Nagasaki F. A case of acute hepatitis with positive autoantibodies who actually had hepatitis e virus infection. Peron J. Fulminant liver failure from acute autochthonous hepatitis e in france: Description of seven patients with acute hepatitis e and encephalopathy. Viral Hepat. Kumar A. Hepatitis e and acute-on-chronic liver failure. Hernaez R. Acute-on-chronic liver failure: An update. Moreau R. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.

Blasco-Perrin H. Shalimar, Kedia S. Acute liver failure due to hepatitis e virus infection is associated with better survival than other etiologies in indian patients. Severity and outcome of acute-on-chronic liver failure is dependent on the etiology of acute hepatic insults: Analysis of patients. Shimakawa Y. Hepatitis e virus infection and acute-on-chronic liver failure in west africa: A case-control study from the gambia.

Vento S. Fulminant hepatitis associated with hepatitis a virus superinfection in patients with chronic hepatitis c. Hepatitis e virus infection: Multiple faces of an underestimated problem. Caron M. Identification of genotype 1 hepatitis e virus in samples from swine in cambodia. Azman A. The incubation period of hepatitis e genotype 1: Insights from pooled analyses of travellers.

Hepatitis e virus infection. Aggarwal R. Duration of viraemia and faecal viral excretion in acute hepatitis e. Naik A. Lack of evidence of hepatitis e virus infection among renal transplant recipients in a disease-endemic area. Feldt T. Hepatitis e virus infections in hiv-infected patients in ghana and cameroon. Agarwala P. Absence of chronic hepatitis e virus infection in liver transplant recipients: Report from a hyperendemic region.

Indian J. Robins A. Case Rep. Ankcorn M. Navaneethan U. Hepatitis e and pregnancy: Understanding the pathogenesis. Hepatitis e virus infection and its associated adverse feto-maternal outcomes among pregnant women in qinhuangdao, china. Fetal Neonatal Med. Jilani N. Hepatitis e virus infection and fulminant hepatic failure during pregnancy. McGovern B. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis c virus genotype 3 infection in hiv-seropositive patients.

Hev in pregnancy: Understanding the crucial role of steroid hormones. Bose P. High viral load and deregulation of the progesterone receptor signaling pathway: Association with hepatitis e-related poor pregnancy outcome. Singh S. Role of oestrogen and its receptors in hev-associated feto-maternal outcomes. Evidence of extrahepatic replication of hepatitis e virus in human placenta. Kar P. A guide to the management of hepatitis e infection during pregnancy.

Expert Rev. Tabatabai J. First case report of an acute hepatitis e subgenotype 3c infection during pregnancy in germany. Anty R. First case report of an acute genotype 3 hepatitis e infected pregnant woman living in south-eastern france. Cirrhosis, liver transplantation and hiv infection are risk factors associated with hepatitis e virus infection.

Hepatitis e virus and chronic hepatitis in organ-transplant recipients. Gerolami R. Chronic hepatitis e with cirrhosis in a kidney-transplant recipient. Chronic hepatitis e in heart transplant recipients. Course and treatment of chronic hepatitis e virus infection in lung transplant recipients.

Ingiliz P. Persisting hepatitis e virus infection leading to liver cirrhosis despite recovery of the immune system in an hiv-infected patient. Acute and persistent hepatitis e virus genotype 3 and 4 infection: Clinical features, pathogenesis, and treatment. Cold Spring Harb. Wang Y.

Chronic hepatitis e in a renal transplant recipient: The first report of genotype 4 hepatitis e virus caused chronic infection in organ recipient. Legrand-Abravanel F. Hepatitis e virus infection without reactivation in solid-organ transplant recipients, france.

How should hepatitis e virus infection be defined in organ-transplant recipients? Meisner S. Definition of chronic hepatitis e after liver transplant conforms to convention. Dalton H. Persistent carriage of hepatitis e virus in patients with hiv infection.

Kaba M. Hepatitis e virus infection in patients infected with the human immunodeficiency virus. Kuniholm M. Acute and chronic hepatitis e virus infection in human immunodeficiency virus-infected U. Chronic hepatitis e in rheumatology and internal medicine patients: A retrospective multicenter european cohort study. Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: Recommendations of the 5th european conference on infections in leukaemia ecil-5 Lancet Infect.

Woolson K. Extra-hepatic manifestations of autochthonous hepatitis e infection. Versluis J. Hepatitis e virus: An underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Von Felden J. The burden of hepatitis e among patients with haematological malignancy: A retrospective european cohort study.

Hepatitis e virus infection and acute non-traumatic neurological injury: A prospective multicentre study. Van Eijk J. Clinical phenotype and outcome of hepatitis e virus-associated neuralgic amyotrophy. Wang L. Association of hepatitis e virus infection and myasthenia gravis: A pilot study. Van den Berg B. Guillain-barre syndrome associated with preceding hepatitis e virus infection. Hepatitis e virus infection in acute non-traumatic neuropathy: A large prospective case-control study in China.

Extrahepatic manifestations and hev, the genotype matters. Soomro M. Virus Res. Geng Y. Detection and assessment of infectivity of hepatitis e virus in urine. Del Bello A. Successful treatment of hepatitis e virus-associated cryoglobulinemic membranoproliferative glomerulonephritis with ribavirin. Huang F. High prevalence of hepatitis e virus in semen of infertile male and causes testis damage. No link between male infertility and hev genotype 3 infection. Goyal R. Ribavirin therapy for hepatitis e virus-induced acute on chronic liver failure: A preliminary report.

Sinclair S. The ribavirin pregnancy registry: An interim analysis of potential teratogenicity at the mid-point of enrollment. Drug Saf. Treatment of severe acute hepatitis e by ribavirin. Acute autochthonous hepatitis e in western patients with underlying chronic liver disease: A role for ribavirin? Treatment of autochthonous acute hepatitis e with short-term ribavirin: A multicenter retrospective study. Factors associated with chronic hepatitis in patients with hepatitis e virus infection who have received solid organ transplants.

Van Tong H. Hepatitis e virus mutations: Functional and clinical relevance. Debing Y. A mutation in the hepatitis e virus rna polymerase promotes its replication and associates with ribavirin treatment failure in organ transplant recipients.

Todt D. In vivo evidence for ribavirin-induced mutagenesis of the hepatitis e virus genome. Mutagenic effects of ribavirin on hepatitis e virus-viral extinction versus selection of fitness-enhancing mutations. Dao Thi V. Sofosbuvir inhibits hepatitis e virus replication in vitro and results in an additive effect when combined with ribavirin. Van der Valk M. Sofosbuvir shows antiviral activity in a patient with chronic hepatitis e virus infection. Todesco E. Chronic hepatitis e in a heart transplant patient: Sofosbuvir and ribavirin regimen not fully effective.

Cornberg M. Efficacy and safety of sofosbuvir monotherapy in patients with chronic hepatitis e-the hepnet sofe pilot study. Biedenkopf N. The natural compound silvestrol is a potent inhibitor of ebola virus replication.

Gong W. Evaluation of antiviral efficacy of chinese traditional medicine babao dan in rabbits infected with hepatitis e virus. Shrestha M. Safety and efficacy of a recombinant hepatitis e vaccine. Safety of the hepatitis e vaccine for pregnant women: A preliminary analysis. Khuroo M. Vertical transmission of hepatitis e virus. Hepatitis e in pregnancy. Support Center Support Center.

External link. Please review our privacy policy. Tropical developing countries of Asia and Africa. Contaminated drinking water. No zoonotic relevance, no chronic infections described. Industrialized nations, worldwide distributed, autochthonous in Europe, North and South America, Australia, large parts of Asia.

Foodborne zoonosis mainly contact or consumption of inadequately cooked pork shellfish deer Strawberries Vegetables spinach, rocket Blood transfusions. The validity of our determined scores is confirmed by comparing them with functional data available for some of the recovered peptides. In congruence with this, we previously observed that both peptides mediate lung transduction but also strongly transduce liver, heart, and kidney.

The specificity of transgene expression in the pulmonary endothelium correlated with vector distribution, which indicates true specificity in gene delivery as opposed to a mere optimization of postentry vector processing. This unprecedented strength and specificity of transgene expression after systemic administration is composed of both, targeting to the lung and detargeting especially from the liver.

Frequently, AAV2 capsid changes sterically close to the site not only result in liver de-targeting but also augment gene expression in the heart. In view of that it is remarkable, that the tropism of the ESGHGYF clone selected by using the technology described here did not show this pattern and was restricted to the lung. The amino acid sequence of the ESGHGYF peptide does not show any striking similarities with one the different lung-homing peptides that have previously been identified by the phage display technique.

This is not surprising and can most likely be explained by the fundamental differences of the library systems that have been used to identify these peptides. The phage display technique allows the selection of well accessible peptides that are terminally fused to the phage's coat protein without being forced into major structural constraints.

In an AAV display library, on the other hand, the peptides are embedded within a structurally very important area of the viral capsid, in which they may be forced into strong physicochemical constraints. Thus, in an AAV display library it is not necessarily the isolated peptide which is being selected for, more likely it is the modified viral capsid being structurally altered by insertion of this peptide.

Although the receptor targeted by the AAV2-ESGHGYF capsid has not been identified yet, the carbohydrates on the endothelial cell surface presumably are essential for specific targeting, since glycans are used as primary attachment receptors by all AAV serotypes analyzed so far. This would not have been the case if the lung-homing was solely explained by a first pass effect. Although the insertion of the ESGHGYF peptide into the AAV2 capsid does not seem to have an positive influence on the antibody reactivity, the AAV2-ESGHGYF vector might very well be a promising candidate for gene therapy, as there are different potential options to circumvent unwanted immune responses in a clinical setting such as plasmapheresis 61 or blocking of antibodies by applying an excess of empty particles.

Thus, choosing the lung as therapeutically highly relevant target, vectors such as the one presented here might be used in gene therapy for disorders like pulmonary hypertension. Our NGS-guided approach of in vivo selection allows unprecedented exploitation of the high potential of random AAV display peptide libraries and could be used to obtain specific vectors for virtually any given target organ.

Preparation of the random AAV display peptide library. Library plasmids were harvested and purified using Qiagen's Plasmid Preparation Kit. Cells were superinfected with Ad5 at an MOI of five plaque-forming units pfu per cell. The final random peptide AAV display library was harvested from the supernatant after 48 hours.

In vivo screening of the random AAV display peptide library. After 48 hours, mice were sacrificed and organs of interest were removed. The PCR-amplified oligonucleotides were used to produce secondary libraries for four further rounds of selection mice were sacrificed 6 days after library injection in round 2—5. Secondary libraries were produced like the primary library as described earlier but without the extra step of producing transfer shuttles.

Data analysis was performed by a custom script see Supplementary Note 1. Vector production and quantification. Four days after transfection, cells were harvested, lysed, and vectors were purified by iodixanol density-gradient ultracentrifugation as previously described.

The oligonucleotide inserts encoding the modified peptides for the alanine scan were synthesized Metabion and further processed as the library inserts described earlier. Animals and vector administration. The peptide competition experiment and GFP reporter gene experiments for immunohistochemistry were performed in 8—12 weeks old SCID mice.

All experiments involving animals were conducted in accordance with the German Animal Protection Code. The protocol was approved by the responsible ethics review board and the local authorities. Assessment of luciferase reporter gene expression in vivo. At day 14, animals were anesthetized with isoflurane. Subsequently, animals were sacrificed, organs of interest were quickly removed and transgene expression images of single organs were taken immediately.

Three-dimensional reconstructions of in vivo luminescence images were obtained by using the DLIT option of the software Living Image 4. To quantify luciferase expression, organs were homogenized in reporter lysis buffer Promega, Madison, WI using a Precelly's 24 tissue homogenizer Peqlab, Erlangen, Germany according to the manufacturer's instructions. Analysis of vector distribution. For quantification of vector genome copy numbers in the circulation, blood was collected by left ventricular puncture and incubated for 10 minutes at room temperature.

PCR efficiency was controlled by a spiked-in plasmid. Immunohistochemistry and histology. Lung tissues were embedded in paraffin. Two-micrometer sections were dewaxed, rehydrated, and used for immunohistochemistry. After washing in phosphate-buffered saline, the sections were incubated for 30 minutes with a secondary biotinylated goat antirabbit antibody Vector Lab. Louis, MO. Selected sections were counterstained with hemalum. In vivo imaging of luminescence mediated by recombinant AAV2 vectors.

Figure S2. Figure S3. Figure S4. Figure S5. Figure S6. Figure S7. Figure S8. Note S1. Bioinformatical data processing. Materials and Methods References. Designed the experiments: J. Performed the experiments: J. Analyzed the data: J. Wrote the manuscript: J. The authors declare that there are no further competing financial interests. Read article at publisher's site DOI : Viruses , 12 4 , 18 Apr Li C , Samulski RJ. Nat Rev Genet , 21 4 , 10 Feb Cited by: 22 articles PMID: Int J Mol Sci , 21 1 , 27 Dec This data has been text mined from the article, or deposited into data resources.

This data has been provided by curated databases and other sources that have cited the article. To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. PLoS One , 4 4 :e, 09 Apr J Gen Virol , 93 pt 10 , 04 Jul Cited by: 7 articles PMID: Nat Biotechnol , 21 9 , 03 Aug Cited by: articles PMID: Michelfelder S , Trepel M.

Adv Genet , , 01 Jan Cited by: 65 articles PMID: Gene Ther , 10 14 , 01 Jul Cited by: 67 articles PMID: Coronavirus: Find the latest articles and preprints. Europe PMC requires Javascript to function effectively. Recent Activity. Recent history Saved searches. Search articles by 'Timo Sieber'. Sieber T 1 ,. Search articles by 'Stefan Michelfelder'. Michelfelder S 1 ,. Search articles by 'Lars Lunding'.

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Share this article Share with email Share with twitter Share with linkedin Share with facebook. Free full text. Mol Ther. Published online Apr Prepublished online Mar PMID: Author information Article notes Copyright and License information Disclaimer. E-mail: ed. Received Oct 5; Accepted Mar This article has been cited by other articles in PMC.

Go to:. Supplementary Methods. Screening the random AAV-display peptide library for lung-targeted capsids in vivo yields a distinct peptide sequence To select specific tissue-targeted AAV2 capsids, an AAV2-displayed random heptamer peptide library was screened in vivo in mice, choosing the lung as the target of interest. Open in a separate window. Figure 1. Figure 2. AAV2 vectors displaying the ESGHGYF peptide mediate strong and specific gene expression in the lung To analyze the in vivo tropism, targeting and control peptides were incorporated into the capsids of AAV vectors carrying a luciferase reporter gene.

Figure 3. Figure 4. ESGHGYF-mediated targeting is based on lung-specific homing of circulating vectors To investigate if the lung-specific transgene expression of intravenously administered ESGHGYF vectors is based on specific homing, we analyzed the vector distribution as early as 2 minutes after injection Figure 5a. Figure 5. Figure 6. Supplementary Methods Click here for additional data file.

Pasqualini, R and Ruoslahti, E Organ targeting in vivo using phage display peptide libraries. Nature : — Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display. J Clin Invest : — Targeting the prostate for destruction through a vascular address. Reversal of obesity by targeted ablation of adipose tissue. Nat Med 10 : — Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy.

Nat Med 15 : — Vascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses. Mol Ther 13 : — Modulation of the immune response by systemic targeting of antigens to lymph nodes. Cancer Res 61 : — A hybrid vector for ligand-directed tumor targeting and molecular imaging. Cell : — Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Ther 15 : — Clinical gene therapy using recombinant adeno-associated virus vectors.

Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 12 : — Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol Ther 20 : — Structurally mapping the diverse phenotype of adeno-associated virus serotype 4.

J Virol 80 : — Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 14 : 45— Efficient transduction of vascular endothelial cells with recombinant adeno-associated virus serotype 1 and 5 vectors.

Hum Gene Ther 16 : — Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther 18 : — Analysis of AAV serotypes mediated gene expression and tropism in mice after systemic injection. Mol Ther 16 : — J Virol 77 : — Directed evolution of adeno-associated virus yields enhanced gene delivery vectors.

Nat Biotechnol 24 : — In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 82 : — DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Exploring protein fitness landscapes by directed evolution. Nat Rev Mol Cell Biol 10 : — Mol Ther 17 : — Directed evolution of adeno-associated virus to an infectious respiratory virus. Directed evolution of a novel adeno-associated virus AAV vector that crosses the seizure-compromised blood-brain barrier BBB.

Mol Ther 18 : — Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Directed evolution of adeno-associated virus AAV as vector for muscle gene therapy. Methods Mol Biol : — Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors.

Circulation : — Engineering adeno-associated virus 2 vectors for targeted gene delivery to atherosclerotic lesions. Development of efficient viral vectors selective for vascular smooth muscle cells. Mol Ther 9 : — A muscle-targeting peptide displayed on AAV2 improves muscle tropism on systemic delivery. Gene Ther 16 : — RGD inclusion in VP3 provides adeno-associated virus type 2 AAV2 -based vectors with a heparan sulfate-independent cell entry mechanism.

Mol Ther 7 : —


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