Publications by authors named "Tanvi Khera"

18 Publications

  • Page 1 of 1

The impact of hepatitis B surface antigen on natural killer cells in patients with chronic hepatitis B infection.

Liver Int 2021 Apr 1. Epub 2021 Apr 1.

Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Background & Aims: During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB).

Methods: 80 CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes.

Results: Compared to the healthy controls, a reshaping of NK cell pool towards more CD56 NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/ml) displayed an activated phenotype with increased expression of activation makers CD38, Granzyme B and proliferation marker Ki-67 while presenting with defective functional responses (MIP-1β, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age.

Conclusions: The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance.
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http://dx.doi.org/10.1111/liv.14885DOI Listing
April 2021

Scheduled Prophylactic 6-Hourly IV AcetaminopheN to Prevent Postoperative Delirium in Older CaRdiac SurgicAl Patients (PANDORA): protocol for a multicentre randomised controlled trial.

BMJ Open 2021 Mar 10;11(3):e044346. Epub 2021 Mar 10.

Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Introduction: Postoperative delirium is common among older cardiac surgery patients. Often difficult to predict and address prophylactically, delirium complicates the postoperative course by increasing morbidity and mortality as well as prolonging both hospital and intensive care unit (ICU) lengths of stay. Based on our pilot trial, we intend to study the effect of scheduled 6-hourly acetaminophen administration for 48 hours post-cardiac surgery with cardiopulmonary bypass (CPB) on the incidence of in-hospital delirium and long-term neurocognitive outcomes. Additionally, effect on duration and severity of delirium, rescue analgesic consumption, acute and chronic pain scores and lengths of hospital and ICU stay will also be explored.

Methods And Analysis: This multicentre, randomised, placebo-controlled, quadruple-blinded trial will include 900 older (>60 years) cardiac surgical patients requiring CPB. Patients meeting the inclusion criteria and not meeting any exclusion criteria will be enrolled at seven centres across the USA with Beth Israel Deaconess Medical Center (BIDMC), Boston, as the central coordinating centre. Additional sites may be included to broaden or speed accrual. The primary outcome measure is the incidence of in-hospital delirium till day 30. Secondary outcomes include the duration and severity of in-hospital delirium, hospital and ICU lengths of stay, postoperative pain scores, postoperative rescue analgesic consumption, postoperative cognitive function and chronic sternal pain. Creation of a biorepository and the use of intraoperative-blinded electroencephalogram (EEG) and cerebral oximetry data will support exploratory endpoints to determine mechanistic predictors of postoperative delirium.

Ethics And Dissemination: This trial is approved and centrally facilitated by the Institutional Review Board at BIDMC. An independent Data Safety and Monitoring Board is responsible for maintaining safety oversight. Protocol # 2019 P00075, V.1.4 (dated 20 October 2020).

Trial Registration Number: NCT04093219.
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http://dx.doi.org/10.1136/bmjopen-2020-044346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949372PMC
March 2021

Distinct Immune imprints of post-Liver transplantation hepatitis C persist despite viral clearance.

Liver Transpl 2021 Feb 28. Epub 2021 Feb 28.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: Recurrence or de novo infection of hepatitis C virus (HCV) after liver-transplantation has been associated with progressive graft hepatitis that can be improved by treatment with novel direct-acting antivirals. Cases of rejection episodes have been described during and after HCV treatment. The evolution of innate and adaptive immune response during and after cure of hepatitis C after liver-transplantation is unknown.

Methods: We here studied 74 protein biomarkers in plasma of liver-transplanted patients receiving antiviral therapy. In addition, deep immune-phenotyping of both the myeloid and lymphoid immune cell subsets in peripheral blood mononuclear cells was performed.

Results: We found that liver-transplanted patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers such as CXCL10, CASP-8, CCL20, CCL19, IFN-gamma, CDCP1, IL-18R1, CXCL11, CCL3, IL8, IL12B, TNFB, CXCL6, OPG, IL10, Flt3L, HGF, uPA, NT-3, CCL4, IL6, TNFRSF9, PD-L1, IL18 and MCP-1 and enrichment of peripheral immune cell subsets unlike transplanted patients without HCV infection. Interestingly, patients that cleared HCV post liver-transplantation did not normalize the altered inflammatory milieu nor did the peripheral immune cell subsets normalize to what would be seen in the absence of HCV recurrence.

Conclusion: Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets post liver-transplantation are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV post-transplantation did not trigger rejection episodes in many patients.
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http://dx.doi.org/10.1002/lt.26031DOI Listing
February 2021

Ocular complications of perioperative anesthesia: a review.

Graefes Arch Clin Exp Ophthalmol 2021 Feb 24. Epub 2021 Feb 24.

Advanced Eye Center, Department of Ophthalmology, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh, 160012, India.

Ocular complications associated with anesthesia in ocular and non-ocular surgeries are rare adverse events which may present with clinical presentations vacillating between easily treatable corneal abrasions to more serious complication such as irreversible bilateral vision loss. In this review, we outline the different techniques of anesthetic delivery in ocular surgeries and highlight the incidence and etiologies of associated injuries. The changes in vision in non-ocular surgeries are mistaken for residual sedation or anesthetics, therefore require high clinical suspicion on part of the treating ophthalmologists, to ensure early diagnosis, adequate and swift management especially in surgeries such as cardiac, spine, head and neck, and some orthopedic procedures, that have a comparatively higher incidence of ocular complications. In this article, we review the literature for reports on the clinical incidence of different ocular complications associated with anesthesia in non-ocular surgeries and outline the current understanding of pathophysiological processes associated with these adverse events.
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http://dx.doi.org/10.1007/s00417-021-05119-xDOI Listing
February 2021

Long-lasting Imprint in the Soluble Inflammatory Milieu despite Early Treatment of Acute Symptomatic Hepatitis C.

J Infect Dis 2021 Jan 31. Epub 2021 Jan 31.

Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Background: Treatment with direct acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C with DAAs may normalize most SIMs.

Methods: In this study, we made use of a unique cohort of acute symptomatic hepatitis C who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay (PEA) measuring 92 proteins.

Results: Profound SIM alterations were observed in acute HCV patients, with marked upregulation of IL-6 and CXCL10 while certain mediators were down-regulated (e.g. MCP-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (e.g. CDCP1, IL-18). Of note, SIMs that were down-regulated before DAA treatment remained suppressed while others that were initially unchanged, declined to lower values during treatment and follow-up (e.g.CD244).

Conclusions: Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu as compared to both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained. Thus, acute HCV-induced changes in the immune system may persist even after a short duration of viremia.
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http://dx.doi.org/10.1093/infdis/jiab048DOI Listing
January 2021

Hepatitis C reference viruses highlight potent antibody responses and diverse viral functional interactions with neutralising antibodies.

Gut 2020 Dec 15. Epub 2020 Dec 15.

Experimental Virology, TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany

Objective: Neutralising antibodies are key effectors of infection-induced and vaccine-induced immunity. Quantification of antibodies' breadth and potency is critical for understanding the mechanisms of protection and for prioritisation of vaccines. Here, we used a unique collection of human specimens and HCV strains to develop HCV reference viruses for quantification of neutralising antibodies, and to investigate viral functional diversity.

Design: We profiled neutralisation potency of polyclonal immunoglobulins from 104 patients infected with HCV genotype (GT) 1-6 across 13 HCV strains representing five viral GTs. Using metric multidimensional scaling, we plotted HCV neutralisation onto neutralisation maps. We employed K-means clustering to guide virus clustering and selecting representative strains.

Results: Viruses differed greatly in neutralisation sensitivity, with J6 (GT2a) being most resistant and SA13 (GT5a) being most sensitive. They mapped to six distinct neutralisation clusters, in part composed of viruses from different GTs. There was no correlation between viral neutralisation and genetic distance, indicating functional neutralisation clustering differs from sequence-based clustering. Calibrating reference viruses representing these clusters against purified antibodies from 496 patients infected by GT1 to GT6 viruses readily identified individuals with extraordinary potent and broadly neutralising antibodies. It revealed comparable antibody cross-neutralisation and diversity between specimens from diverse viral GTs, confirming well-balanced reporting of HCV cross-neutralisation across highly diverse human samples.

Conclusion: Representative isolates from six neutralisation clusters broadly reconstruct the functional HCV neutralisation space. They enable high resolution profiling of HCV neutralisation and they may reflect viral functional and antigenic properties important to consider in HCV vaccine design.
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http://dx.doi.org/10.1136/gutjnl-2020-321190DOI Listing
December 2020

Liver-expressed and limit hepatitis C virus cross-species transmission to mice.

Sci Adv 2020 Nov 4;6(45). Epub 2020 Nov 4.

Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, Twincore, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany.

Hepatitis C virus (HCV) has no animal reservoir, infecting only humans. To investigate species barrier determinants limiting infection of rodents, murine liver complementary DNA library screening was performed, identifying transmembrane proteins Cd302 and Cr1l as potent restrictors of HCV propagation. Combined ectopic expression in human hepatoma cells impeded HCV uptake and cooperatively mediated transcriptional dysregulation of a noncanonical program of immunity genes. Murine hepatocyte expression of both factors was constitutive and not interferon inducible, while differences in liver expression and the ability to restrict HCV were observed between the murine orthologs and their human counterparts. Genetic ablation of endogenous expression in human HCV entry factor transgenic mice increased hepatocyte permissiveness for an adapted HCV strain and dysregulated expression of metabolic process and host defense genes. These findings highlight human-mouse differences in liver-intrinsic antiviral immunity and facilitate the development of next-generation murine models for preclinical testing of HCV vaccine candidates.
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http://dx.doi.org/10.1126/sciadv.abd3233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673688PMC
November 2020

Reversal of Immunity After Clearance of Chronic HCV Infection-All Reset?

Front Immunol 2020 8;11:571166. Epub 2020 Oct 8.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Chronic viral infections cause deterioration of our immune system. However, since persistent infections rarely can be eliminated, the reinvigoration capacity of an exhausted immune system has remained largely elusive. Chronic hepatitis C virus (HCV) infection can since some years be effectively cured with novel direct acting antiviral agents. Thus, it is now possible to study reversal of immunity in patients that are cured from a long-lasting chronic infection. We here highlight recent developments in the analysis of various immune cell populations during and after clearance of HCV infection. Surprisingly, whereas reinvigoration of certain immune traits clearly can be seen, many features of immune exhaustion persist over time after viral elimination. Thus, a long-term chronic insult might result in irreversible damage to our immune system. This will be important to consider in therapeutic vaccination efforts against chronic infection and in the development of immunotherapy based strategies against cancer.
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http://dx.doi.org/10.3389/fimmu.2020.571166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578424PMC
October 2020

Ultrasound-Guided Pecto-Intercostal Fascial Block for Postoperative Pain Management in Cardiac Surgery: A Prospective, Randomized, Placebo-Controlled Trial.

J Cardiothorac Vasc Anesth 2021 Mar 24;35(3):896-903. Epub 2020 Jul 24.

Center for Anesthesia and Research Excellence, Department of Anesthesia Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA; Harvard Medical School, Boston, MA. Electronic address:

Objective: To explore the effect of pecto-intercostal fascial plane block (PIFB) on postoperative opioid requirements, pain scores, lengths of intensive care unit and hospital stays and incidence of postoperative delirium in cardiac surgical patients.

Design: Single- center, prospective, randomized (1:1), quadruple- blinded, placebo-controlled trial.

Setting: Single center, tertiary- care center.

Participants: The study comprised 80 adult cardiac surgical patients (age >18 y) requiring median sternotomy.

Intervention: Patients were randomly assigned to receive ultrasound-guided PIFB, with either 0.25% bupivacaine or placebo, on postoperative days 0 and 1.

Measurements And Main Results: Of the 80 patients randomized, the mean age was 65.78 ± 8.73 in the bupivacaine group and 65.70 ± 9.86 in the placebo group (p = 0.573). Patients receiving PIFB with 0.25% bupivacaine showed a statistically significant reduction in visual analog scale scores (4.8 ± 2.7 v 5.1 ± 2.6; p < 0.001), but the 48-hour cumulative opioid requirement computed as morphine milligram equivalents was similar (40.8 ± 22.4 mg v 49.1 ± 26.9 mg; p = 0.14). There was no difference in the incidence of postoperative delirium between the groups evaluated using the 3-minute diagnostic Confusion Assessment Method (3/40 [7.5%] v 5/40 [12.5%] placebo; p = 0.45).

Conclusion: Patients who received PIFB with bupivacaine showed a decline in cumulative opioid consumption postoperatively, but this difference between the groups was not statistically significant. Low incidence of complications and improvement in visual analog scale pain scores suggested that the PIFB can be performed safely in this population and warrants additional studies with a larger sample size.
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http://dx.doi.org/10.1053/j.jvca.2020.07.058DOI Listing
March 2021

A Case Report of Nonalcoholic Gayet-Wernicke Encephalopathy: Don't Miss Thiamine.

A A Pract 2020 Jun;14(8):e01230

From the Department of Anaesthesia and Intensive Care, Government Medical College and Hospital, Chandigarh, India.

Gayet-Wernicke encephalopathy (WE) is an acute neurological disorder resulting from deficiency of thiamine, commonly related to chronic abuse of alcohol, but frequently missed or overlooked as a diagnosis when a nonalcoholic patient presents with atypical signs and symptoms of the disease. The diagnosis of the disease is clinical, and confirmation is done by magnetic resonance imaging. We aim to highlight a case of WE in a nonalcoholic postoperative surgical patient receiving total parental nutrition where high-dose intravenous administration of thiamine in time mitigated the symptoms of disease and prevented permanent neurological sequelae. We spotlight the significance of adequate thiamine for postoperative malnourished surgical patients.
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http://dx.doi.org/10.1213/XAA.0000000000001230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323824PMC
June 2020

Autoimmune hepatitis induction can occur in the liver.

Liver Int 2020 02 1;40(2):377-381. Epub 2019 Dec 1.

Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.

The priming of T cells in the liver is widely accepted. Nonetheless, it is controversial whether immune activation in autoimmune hepatitis (AIH) occurs in the liver or in the spleen. To address this issue, we splenectomized mice and induced experimental murine AIH (emAIH) with an adenovirus (Ad)-expressing formiminotransferase cyclodeaminase (FTCD). Post-splenectomy, the experimental mice developed emAIH to a higher extent than the control mice. In addition, splenectomized mice harboured more intrahepatic B cells and a disproportionately small number of regulatory T cells (Tregs) within a reduced T cell population at the site of inflammation. These results imply that the spleen is not the site of AIH induction. In contrast, the spleen seems to have a protective function since the pathological score was more severe in splenectomized animals. These findings have important implications for the aetiology of AIH.
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http://dx.doi.org/10.1111/liv.14296DOI Listing
February 2020

Yellow Fever: Integrating Current Knowledge with Technological Innovations to Identify Strategies for Controlling a Re-Emerging Virus.

Viruses 2019 10 17;11(10). Epub 2019 Oct 17.

Division of Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany.

Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host-virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease.
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http://dx.doi.org/10.3390/v11100960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832525PMC
October 2019

Formula to memorise LMA ProSeal™ intracuff volume.

Indian J Anaesth 2019 Jul;63(7):596-597

Department of Anaesthesia and Intensive Care, Government Medical College and Hospital, Chandigarh, India.

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http://dx.doi.org/10.4103/ija.IJA_124_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644198PMC
July 2019

Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants.

J Hepatol 2019 04 13;70(4):593-602. Epub 2018 Nov 13.

Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. Electronic address:

Background & Aims: Induction of cross-reactive antibodies targeting conserved epitopes of the envelope proteins E1E2 is a key requirement for an hepatitis C virus vaccine. Conserved epitopes like the viral CD81-binding site are targeted by rare broadly neutralizing antibodies. However, these viral segments are occluded by variable regions and glycans. We aimed to identify antigens exposing conserved epitopes and to characterize their immunogenicity.

Methods: We created hepatitis C virus variants with mutated glycosylation sites and/or hypervariable region 1 (HVR1). Exposure of the CD81 binding site and conserved epitopes was quantified by soluble CD81 and antibody interaction and neutralization assays. E2 or E1-E2 heterodimers with mutations causing epitope exposure were used to immunize mice. Vaccine-induced antibodies were examined and compared with patient-derived antibodies.

Results: Mutant viruses bound soluble CD81 and antibodies targeting the CD81 binding site with enhanced efficacy. Mice immunized with E2 or E1E2 heterodimers incorporating these modifications mounted strong, cross-binding, and non-interfering antibodies. E2-induced antibodies neutralized the autologous virus but they were not cross-neutralizing.

Conclusions: Viruses lacking the HVR1 and selected glycosylation sites expose the CD81 binding site and cross-neutralization antibody epitopes. Recombinant E2 proteins carrying these modifications induce strong cross-binding but not cross-neutralizing antibodies.

Lay Summary: Conserved viral epitopes can be made considerably more accessible for binding of potently neutralizing antibodies by deletion of hypervariable region 1 and selected glycosylation sites. Recombinant E2 proteins carrying these mutations are unable to elicit cross-neutralizing antibodies suggesting that exposure of conserved epitopes is not sufficient to focus antibody responses on production of cross-neutralizing antibodies.
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http://dx.doi.org/10.1016/j.jhep.2018.11.003DOI Listing
April 2019

Hepatitis E virus replication and interferon responses in human placental cells.

Hepatol Commun 2018 02 8;2(2):173-187. Epub 2018 Jan 8.

Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection Research Hannover Germany.

Hepatitis E virus (HEV) is a member of the genus in the family and the causative agent of hepatitis E in humans. HEV is a major health problem in developing countries, causing mortality rates up to 25% in pregnant women. However, these cases are mainly reported for HEV genotype (gt)1, while gt3 infections are usually associated with subclinical courses of disease. The pathogenic mechanisms of adverse maternal and fetal outcome during pregnancy in HEV-infected pregnant women remain elusive. In this study, we observed that HEV is capable of completing the full viral life cycle in placental-derived cells (JEG-3). Following transfection of JEG-3 cells, HEV replication of both HEV gts could be observed. Furthermore, determination of extracellular and intracellular viral capsid levels, infectivity, and biophysical properties revealed production of HEV infectious particles with similar characteristics as in liver-derived cells. Viral entry was analyzed by infection of target cells and detection of either viral RNA or staining for viral capsid protein by immunofluorescence. HEV gt1 and gt3 were efficiently inhibited by ribavirin in placental as well as in human hepatoma cells. In contrast, interferon-α sensitivity was lower in the placental cells compared to liver cells for gt1 but not gt3 HEV. Simultaneous determination of interferon-stimulated gene expression levels demonstrated an efficient HEV-dependent restriction in JEG-3. : We showed differential tissue-specific host responses to HEV genotypes, adding to our understanding of the mechanisms contributing to fatal outcomes of HEV infections during pregnancy. Using this cell-culture system, new therapeutic options for HEV during pregnancy can be identified and evaluated. ( 2018;2:173-187).
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http://dx.doi.org/10.1002/hep4.1138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796324PMC
February 2018

Tracking HCV protease population diversity during transmission and susceptibility of founder populations to antiviral therapy.

Antiviral Res 2017 Mar 3;139:129-137. Epub 2017 Jan 3.

Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany. Electronic address:

Due to the highly restricted species-tropism of Hepatitis C virus (HCV) a limited number of animal models exist for pre-clinical evaluation of vaccines and antiviral compounds. The human-liver chimeric mouse model allows heterologous challenge with clinically relevant strains derived from patients. However, to date, the transmission and longitudinal evolution of founder viral populations in this model have not been characterized in-depth using state-of-the-art sequencing technologies. Focusing on NS3 protease encoding region of the viral genome, mutant spectra in a donor inoculum and individual recipient mice were determined via Illumina sequencing and compared, to determine the effects of transmission on founder viral population complexity. In all transmissions, a genetic bottleneck was observed, although diverse viral populations were transmitted in each case. A low frequency cloud of mutations (<1%) was detectable in the donor inoculum and recipient mice, with single nucleotide variants (SNVs) > 1% restricted to a subset of nucleotides. The population of SNVs >1% was reduced upon transmission while the low frequency SNV cloud remained stable. Fixation of multiple identical synonymous substitutions was apparent in independent transmissions, and no evidence for reversion of T-cell epitopes was observed. In addition, susceptibility of founder populations to antiviral therapy was assessed. Animals were treated with protease inhibitor (PI) monotherapy to track resistance associated substitution (RAS) emergence. Longitudinal analyses revealed a decline in population diversity under therapy, with no detectable RAS >1% prior to therapy commencement. Despite inoculation from a common source and identical therapeutic regimens, unique RAS emergence profiles were identified in different hosts prior to and during therapeutic failure, with complex mutational signatures at protease residues 155, 156 and 168 detected. Together these analyses track viral population complexity at high-resolution in the human-liver chimeric mouse model post-transmission and under therapeutic intervention, revealing novel insights into the evolutionary processes which shape viral protease population composition at various critical stages of the viral life-cycle.
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http://dx.doi.org/10.1016/j.antiviral.2017.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292934PMC
March 2017

Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design.

Viruses 2015 Jul 17;7(7):3995-4046. Epub 2015 Jul 17.

Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.

In the 26 years since the discovery of Hepatitis C virus (HCV) a major global research effort has illuminated many aspects of the viral life cycle, facilitating the development of targeted antivirals. Recently, effective direct-acting antiviral (DAA) regimens with >90% cure rates have become available for treatment of chronic HCV infection in developed nations, representing a significant advance towards global eradication. However, the high cost of these treatments results in highly restricted access in developing nations, where the disease burden is greatest. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in at risk groups and resource constrained settings due to limited surveillance. Consequently a prophylactic vaccine is much needed. The HCV envelope glycoproteins E1 and E2 are located on the surface of viral lipid envelope, facilitate viral entry and are the targets for host immunity, in addition to other functions. Unfortunately, the extreme global genetic and antigenic diversity exhibited by the HCV glycoproteins represents a significant obstacle to vaccine development. Here we review current knowledge of HCV envelope protein structure, integrating knowledge of genetic, antigenic and functional diversity to inform rational immunogen design.
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http://dx.doi.org/10.3390/v7072809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517138PMC
July 2015