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Article ; Online: Establishment of mice with inheritable susceptibility to productive hepatitis C virus infection.

Uprichard, Susan L

2014 Volume 59, Issue 5, Page(s) 2043–2046

MeSH term(s)	Animals ; Disease Models, Animal ; Genetic Engineering ; Hepacivirus/physiology ; Hepatitis C/genetics ; Hepatitis C/virology ; Humans ; Virus Replication
Language	English
Publishing date	2014-05
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.26949
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Zs.A 1660: Show issues

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Article ; Online: Sequencing during Times of Change: Evaluating SARS-CoV-2 Clinical Samples during the Transition from the Delta to Omicron Wave.

Feng, Shuchen / Ali, Mudassir S / Evdokimova, Monika / Reid, Gail E / Clark, Nina M / Uprichard, Susan L / Baker, Susan C

Viruses

2022 Volume 14, Issue 7

Abstract: The pandemic of SARS-CoV-2 is characterized by the emergence of new variants of concern (VOCs) that supplant previous waves of infection. Here, we describe our investigation of the lineages and host-specific mutations identified in a particularly ... ...

Abstract	The pandemic of SARS-CoV-2 is characterized by the emergence of new variants of concern (VOCs) that supplant previous waves of infection. Here, we describe our investigation of the lineages and host-specific mutations identified in a particularly vulnerable population of predominantly older and immunosuppressed SARS-CoV-2-infected patients seen at our medical center in Chicago during the transition from the Delta to Omicron wave. We compare two primer schemes, ArticV4.1 and VarSkip2, used for short read amplicon sequencing, and describe our strategy for bioinformatics analysis that facilitates identifying lineage-associated mutations and host-specific mutations that arise during infection. This study illustrates the ongoing evolution of SARS-CoV-2 VOCs in our community and documents novel constellations of mutations that arise in individual patients. The ongoing evaluation of the evolution of SARS-CoV-2 during this pandemic is important for informing our public health strategies.
MeSH term(s)	COVID-19/epidemiology ; Humans ; Mutation ; SARS-CoV-2/genetics ; Sequence Analysis
Language	English
Publishing date	2022-06-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14071408
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Article: Hepatitis C virus Cell-to-cell Spread Assay.

Barretto, Naina / Uprichard, Susan L

Bio-protocol

2017 Volume 4, Issue 24

Abstract: Hepatitis C virus (HCV) can infect naïve cells via entry of "cell-free" extracellular virus or direct "cell-to-cell" transmission. Here, we describe an assay for detecting HCV cell-to-cell transmission, using a non-growing cell culture system that avoids ...

Abstract	Hepatitis C virus (HCV) can infect naïve cells via entry of "cell-free" extracellular virus or direct "cell-to-cell" transmission. Here, we describe an assay for detecting HCV cell-to-cell transmission, using a non-growing cell culture system that avoids confounding effects of cell growth. The assay consists of infecting a small number of cells in a confluent monolayer and then blocking subsequent cell-free extracellular virions with a neutralizing antibody such that only cell-to-cell transmission may occur. Under these conditions, incubation at 37 °C results in the formation of infected cell foci. The extent of cell-to-cell spread can then be determined by counting the number of cells in each focus. The assay may be modified to assess the effects of inhibitors and/or specific cellular genes on cell-to-cell spread of HCV.
Language	English
Publishing date	2017-11-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.1365
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Article ; Online: Inhibition of hepatitis C entry: too soon to dismiss while many are still being denied treatment.

Uprichard, Susan L / Sainz, Bruno

Gut

2015 Volume 64, Issue 4, Page(s) 690–691

MeSH term(s)	Animals ; Antiviral Agents/therapeutic use ; Hepacivirus/drug effects ; Hepatitis C/drug therapy ; Humans ; Virus Internalization/drug effects
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2015-04
Publishing country	England
Document type	Comment ; Letter
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2014-308396
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Article ; Online: Hepatitis C virus experimental model systems and antiviral drug research.

Uprichard, Susan L

Virologica Sinica

2010 Volume 25, Issue 4, Page(s) 227–245

Abstract: An estimated 130 million people worldwide are chronically infected with hepatitis C virus (HCV) making it a leading cause of liver disease worldwide. Because the currently available therapy of pegylated interferon-alpha and ribavirin is only effective in ...

Abstract	An estimated 130 million people worldwide are chronically infected with hepatitis C virus (HCV) making it a leading cause of liver disease worldwide. Because the currently available therapy of pegylated interferon-alpha and ribavirin is only effective in a subset of patients, the development of new HCV antivirals is a healthcare imperative. This review discusses the experimental models available for HCV antiviral drug research, recent advances in HCV antiviral drug development, as well as active research being pursued to facilitate development of new HCV-specific therapeutics.
MeSH term(s)	Animals ; Antiviral Agents/therapeutic use ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Hepacivirus/drug effects ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/virology ; Humans ; Microbial Sensitivity Tests/methods
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2010-07-28
Publishing country	China
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1011219-4
ISSN	1995-820X ; 1000-3223 ; 1003-5125
ISSN (online)	1995-820X
ISSN	1000-3223 ; 1003-5125
DOI	10.1007/s12250-010-3134-0
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Zs.A 4175: Show issues

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Article: Hepatitis delta virus RNA decline post inoculation in human NTCP transgenic mice is biphasic.

Maya, Stephanie / Hershkovich, Leeor / Cardozo-Ojeda, E Fabian / Shirvani-Dastgerdi, Elham / Srinivas, Jay / Shekhtman, Louis / Uprichard, Susan L / Berneshawi, Andrew R / Cafiero, Thomas R / Dahari, Harel / Ploss, Alexander

bioRxiv : the preprint server for biology

2023

Abstract: Background and aims: Chronic infection with hepatitis B and hepatitis delta viruses (HDV) is considered the most serious form of viral hepatitis due to more severe manifestations of and accelerated progression to liver fibrosis, cirrhosis, and ... ...

Abstract	Background and aims: Chronic infection with hepatitis B and hepatitis delta viruses (HDV) is considered the most serious form of viral hepatitis due to more severe manifestations of and accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. There is no FDA-approved treatment for HDV and current interferon-alpha treatment is suboptimal. We characterized early HDV kinetics post inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. Methods: We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor - human sodium taurocholate co-transporting peptide (hNTCP). Results: Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 18 minutes (standard error, SE: 2.4), binds to non-specific cells with a rate of 0.06 hour Conclusions: Understanding early HDV-host kinetics will inform pre-clinical therapeutic kinetic studies on how the efficacy of anti-HDV therapeutics can be affected by early kinetics of viral decline. Lay summary: The persistence phase of HDV infection has been studied in some animal models, however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics. Understanding the kinetics of viral clearance in the blood can aid pre-clinical development and testing models for anti-HDV therapeutics.
Language	English
Publishing date	2023-02-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.17.528964
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Article ; Online: Hepatitis delta virus RNA decline post-inoculation in human NTCP transgenic mice is biphasic.

mBio

2023 Volume 14, Issue 4, Page(s) e0100823

Abstract: Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. We characterized early HDV ... ...

Abstract	Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. We characterized early HDV kinetics post-inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor-human sodium taurocholate co-transporting polypeptide (hNTCP). Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific-binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 35 minutes (standard error, SE: 6.3), binds to non-specific cells with a rate of 0.05 per hour (SE: 0.01), and returns as free virus with a rate of 0.11 per hour (SE: 0.02). Characterizing early HDV-host kinetics elucidates how quickly HDV is either cleared or bound depending on the immunological background and hNTCP presence. IMPORTANCE The persistence phase of HDV infection has been studied in some animal models; however, the early kinetics of HDV
MeSH term(s)	Humans ; Mice ; Animals ; Mice, Transgenic ; Hepatitis Delta Virus/genetics ; Kinetics ; Mice, Inbred C57BL ; RNA ; Liver Neoplasms
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.01008-23
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Article ; Online: Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics.

Hailegiorgis, Atesmachew / Ishida, Yuji / Collier, Nicholson / Imamura, Michio / Shi, Zhenzhen / Reinharz, Vladimir / Tsuge, Masataka / Barash, Danny / Hiraga, Nobuhiko / Yokomichi, Hiroshi / Tateno, Chise / Ozik, Jonathan / Uprichard, Susan L / Chayama, Kazuaki / Dahari, Harel

PLoS computational biology

2023 Volume 19, Issue 8, Page(s) e1011309

Abstract: Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic ... ...

Abstract	Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3-4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.
MeSH term(s)	Animals ; Mice ; Kinetics ; Virus Replication ; DNA, Viral ; Hepatitis B ; Hepatitis B virus/genetics ; Virion/physiology
Chemical Substances	DNA, Viral
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1011309
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Article ; Online: HCV Spread Kinetics Reveal Varying Contributions of Transmission Modes to Infection Dynamics.

Durso-Cain, Karina / Kumberger, Peter / Schälte, Yannik / Fink, Theresa / Dahari, Harel / Hasenauer, Jan / Uprichard, Susan L / Graw, Frederik

Viruses

2021 Volume 13, Issue 7

Abstract: The hepatitis C virus (HCV) is capable of spreading within a host by two different transmission modes: cell-free and cell-to-cell. However, the contribution of each of these transmission mechanisms to HCV spread is unknown. To dissect the contribution of ...

Abstract	The hepatitis C virus (HCV) is capable of spreading within a host by two different transmission modes: cell-free and cell-to-cell. However, the contribution of each of these transmission mechanisms to HCV spread is unknown. To dissect the contribution of these different transmission modes to HCV spread, we measured HCV lifecycle kinetics and used an in vitro spread assay to monitor HCV spread kinetics after a low multiplicity of infection in the absence and presence of a neutralizing antibody that blocks cell-free spread. By analyzing these data with a spatially explicit mathematical model that describes viral spread on a single-cell level, we quantified the contribution of cell-free, and cell-to-cell spread to the overall infection dynamics and show that both transmission modes act synergistically to enhance the spread of infection. Thus, the simultaneous occurrence of both transmission modes represents an advantage for HCV that may contribute to viral persistence. Notably, the relative contribution of each viral transmission mode appeared to vary dependent on different experimental conditions and suggests that viral spread is optimized according to the environment. Together, our analyses provide insight into the spread dynamics of HCV and reveal how different transmission modes impact each other.
MeSH term(s)	Cell Line, Tumor ; Hepacivirus/physiology ; Hepatitis C/physiopathology ; Hepatitis C/virology ; Host Microbial Interactions ; Humans ; Kinetics ; Models, Theoretical ; Virus Internalization
Language	English
Publishing date	2021-07-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13071308
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Article: Sequencing during Times of Change: Evaluating SARS-CoV-2 Clinical Samples during the Transition from the Delta to Omicron Wave

Feng, Shuchen / Ali, Mudassir S. / Evdokimova, Monika / Reid, Gail E. / Clark, Nina M. / Uprichard, Susan L. / Baker, Susan C.

Viruses. 2022 June 28, v. 14, no. 7

2022

Abstract	The pandemic of SARS-CoV-2 is characterized by the emergence of new variants of concern (VOCs) that supplant previous waves of infection. Here, we describe our investigation of the lineages and host-specific mutations identified in a particularly vulnerable population of predominantly older and immunosuppressed SARS-CoV-2-infected patients seen at our medical center in Chicago during the transition from the Delta to Omicron wave. We compare two primer schemes, ArticV4.1 and VarSkip2, used for short read amplicon sequencing, and describe our strategy for bioinformatics analysis that facilitates identifying lineage-associated mutations and host-specific mutations that arise during infection. This study illustrates the ongoing evolution of SARS-CoV-2 VOCs in our community and documents novel constellations of mutations that arise in individual patients. The ongoing evaluation of the evolution of SARS-CoV-2 during this pandemic is important for informing our public health strategies.
Keywords	Severe acute respiratory syndrome coronavirus 2 ; at-risk population ; bioinformatics ; evolution ; host specificity ; medical facilities ; pandemic ; public health
Language	English
Dates of publication	2022-0628
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v14071408
Database	NAL-Catalogue (AGRICOLA)

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