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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Development of in vitro and in vivo Systems for the Evaluation of Products for the Prevention and Detection of Hepatitis B, C and Dengue Viruses in the Blood Supply

Principal Investigator: Deborah R. Taylor, PhD
Office / Division / Lab: OBRR / DETTD / LEP


General Overview

The aim of our work is to help to prepare the U.S. for the possibility of future infectious disease outbreaks, either from natural disease emergence or from accidental or intentional (bioterrorism) release. Our laboratory has developed new methods and reagents that are enabling us to learn more about the pathogenesis and control of three emerging infectious viruses: Hepatitis C virus (HCV), Dengue virus, and SARS virus.


The virus that causes Hepatitis C (HCV) currently infects nearly 2% of the world's population. HCV chronically infects nearly everyone who is exposed to the virus, causing liver disease that can lead to liver failure and liver cancer. Disease associated with HCV infection is the leading cause of liver transplant in the United States. There is no vaccine for HCV and treatment for the disease is not only largely ineffective and expensive, but also generally causes severe side effects.

Because blood collection facilities use tests to screen for HCV, there are very few cases of transfusion-related transmission. However, the virus still poses a potential threat to the blood supply because it is an RNA virus. RNA viruses mutate frequently and many of the resulting, changed viruses survive and expand their numbers, making it difficult for existing tests to "recognize" them. Thus, these variants may escape detection. We are currently developing new techniques to grow novel strains of HCV and working to make highly sensitive tests that can detect its presence.

Dengue is a mosquito-borne virus and the most common vector-borne virus worldwide. (Vectors are insects or other animals that transmit infectious organisms through biting or other means). More than 2.5 billion people are at risk for acquiring dengue. Some individuals with dengue have no symptoms, while others suffer symptoms ranging from mild fever to severe hemorrhagic disease (internal bleeding) and/or shock syndrome that causes about 24,000 deaths each year. The incidence of dengue has increased in North America and Puerto Rico in recent years and might threaten the U.S. blood supply. Our laboratory is growing dengue virus and studying features of the virus that affect its pathogenesis in order to develop and evaluate diagnostic and blood screening assays.

SARS virus infections cause severe respiratory problems and is fatal in 10% of cases. The virus can spread quickly: it was first reported in China in the winter of 2003 and by July had spread to 29 countries, having infected more than 8,000 people and leaving 774 people dead. There is currently no vaccine or effective treatment available for SARS. We study the replication of the SARS virus and its ribosome (protein-making machinery) in order to understand how the virus causes disease and to evaluate attenuated (weakened) and recombinant (genetically engineered) forms of this virus that might be useful for making a vaccine against it.


Scientific Overview

Our laboratory focuses on improving the understanding of how viruses interact with host cells. This information will enable researchers to develop improved therapies that serve to control virus infection. We are trying to understand how viruses evade the innate immune system and how they regulate their own replication in the presence of the host antiviral response.

HCV:

The HCV field has been hampered by the lack of an in vitro cell culture system for growth of the virus. Recently, a system was developed using a recombinant form of an unusual strain of the virus. This is not the most drug-resistant of HCV strains and does not respond to antiviral therapeutics as expected for this strain. Our program has established a cell culture system for growing infectious hepatitis C virus (HCV) from human blood in culture. This system will enable the growth of viruses that can be used in vaccine preparations, and for the study of viral pathogenesis, growing viruses for use as panel members, the development of pathogen inactivation methods, and detecting products contaminated with HCV.

Dengue:

Our laboratory is assembling lot release panels for the evaluation and development of diagnostic and blood screening assays. Additionally, we are using a mouse model of dengue virus infection that may be used to test vaccinogens and evaluate correlates of immunity. This includes the study of innate immune pathways in control of dengue viruses in the infected host.

SARS:

Virus studies have included serological and nucleic acid detection of virus and characterization of several techniques for inactivating SARS-CoV, including techniques to inactivate virus in blood products, such as UV inactivation and pasteurization. We study the replication of the SARS virus and its novel ribosome binding structure in order to understand viral pathogenesis and test potential antiviral therapeutics.


Publications

Viral Immunol 2013 Apr;26(2):126-32
Immunogenicity and Protection Efficacy of Monomeric and Trimeric Recombinant SARS Coronavirus Spike Protein Subunit Vaccine Candidates.
Li J, Ulitzky L, Silberstein E, Taylor DR, Viscidi R

Nucleic Acids Res 2013 Feb 1;41(4):2594-608
RNA dimerization plays a role in ribosomal frameshifting of the SARS coronavirus.
Ishimaru D, Plant EP, Sims AC, Yount BL Jr, Roth BM, Eldho NV, Pérez-Alvarado GC, Armbruster DW, Baric RS, Dinman JD, Taylor DR, Hennig M

Viruses 2013 Jan 18;5(1):279-94
Altering SARS coronavirus frameshift efficiency affects genomic and subgenomic RNA production.
Plant EP, Sims AC, Baric RS, Dinman JD, Taylor DR

Arch Virol 2012 Nov;157(11):2095-104
Biochemical characterization of a recombinant SARS coronavirus nsp12 RNA-dependent RNA polymerase capable of copying viral RNA templates.
Ahn DG, Choi JK, Taylor DR, Oh JW

Vox Sang 2012 Aug;103(2):99-106
Distribution of hepatitis C virus in circulating blood components from blood donors.
Chancey C, Winkelman V, Foley JB, Silberstein E, Teixeira-Carvalho A, Taylor DR, Rios M

Antiviral Res 2011 Jul;91(1):1-10
Interference of ribosomal frameshifting by antisense peptide nucleic acids suppresses SARS coronavirus replication.
Ahn DG, Lee W, Choi JK, Kim SJ, Plant EP, Almazán F, Taylor DR, Enjuanes L, Oh JW

J Virol 2010 May;84(9):4330-40
Achieving a Golden Mean: Mechanisms by Which Coronaviruses Ensure Synthesis of the Correct Stoichiometric Ratios of Viral Proteins.
Plant EP, Rakauskaite R, Taylor DR, Dinman JD

PLoS Pathog 2010 May 20;6(5):e1000910
Persistent growth of a human plasma-derived hepatitis C virus genotype 1b isolate in cell culture.
Silberstein E, Mihalik K, Ulitzky L, Plant EP, Puig M, Gagneten S, Yu MY, Kaushik-Basu N, Feinstone SM, Taylor DR

Antivir Chem Chemother 2009 Sep 25;20(1):19-36
Characterization of aurintricarboxylic acid as a potent hepatitis C virus replicase inhibitor.
Chen Y, Bopda-Waffo A, Basu A, Krishnan R, Silberstein E, Taylor DR, Talele TT, Arora P, Kaushik-Basu N

Front Biosci 2009 Jun 1;14:4950-61
Innate immunity and hepatitis C virus: eluding the host cell defense.
Taylor DR, Silberstein E

Front Biosci 2008 May 1;13:4873-81
The role of programmed-1 ribosomal frameshifting in coronavirus propagation.
Plant EP, Dinman JD

J Infect Dis 2007 Nov 1;196(9):1329-38
Severe acute respiratory syndrome coronavirus infection in vaccinated ferrets.
Darnell ME, Plant EP, Watanabe H, Byrum R, St Claire M, Ward JM, Taylor DR

Transfusion 2006 Oct;46(10):1770-7
Evaluation of inactivation methods for severe acute respiratory syndrome coronavirus in noncellular blood products.
Darnell ME, Taylor DR

Vaccine 2006 Feb 13;24(7):863-71
Obstacles and advances in SARS vaccine development.
Taylor DR

J Virol 2005 May;79(10):6291-8
New Antiviral Pathway That Mediates Hepatitis C Virus Replicon Interferon Sensitivity through ADAR1.
Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM

J Virol Methods 2004 Oct;121(1):85-91
Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV.
Darnell ME, Subbarao K, Feinstone SM, Taylor DR

J Virol 2004 Sep;78(18):9782-9
Long-term persistence of infection in chimpanzees inoculated with an infectious hepatitis C virus clone is associated with a decrease in the viral amino Acid substitution rate and low levels of heterogeneity.
Fernandez J, Taylor D, Morhardt DR, Mihalik K, Puig M, Rice CM, Feinstone SM, Major ME

 

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