Influence of host resistance on viral adaptation: hepatitis C virus as a case study

ABSTRACTHepatitis C virus (HCV) species tropism is incompletely understood. We have previously shown that at the level of entry, human CD81 and occludin (OCLN) comprise the minimal set of human factors needed for viral uptake into murine cells. As an alternative approach to genetic humanization, species barriers can be overcome by adapting HCV to use the murine orthologues of these entry factors. We previously generated a murine tropic HCV (mtHCV or Jc1/mCD81) strain harboring three mutations within the viral envelope proteins that allowed productive entry into mouse cell lines. In this study, we aimed to characterize the ability of mtHCV to enter and infect mouse hepatocytesin vivoandin vitro. Using a highly sensitive, Cre-activatable reporter, we demonstrate that mtHCV can enter mouse hepatocytesin vivoin the absence of any human cofactors. Viral entry still relied on expression of mouse CD81 and SCARB1 and was more efficient when mouse CD81 and OCLN were overexpressed. HCV entry could be significantly reduced in the presence of anti-HCV E2 specific antibodies, suggesting that uptake of mtHCV is dependent on viral glycoproteins. Despite mtHCV’s ability to enter murine hepatocytesin vivo, we did not observe persistent infection, even in animals with severely blunted type I and III interferon signaling and impaired adaptive immune responses. Altogether, these results establish proof of concept that the barriers limiting HCV species tropism can be overcome by viral adaptation. However, additional viral adaptations will likely be needed to increase the robustness of a murine model system for hepatitis C.IMPORTANCEAt least 150 million individuals are chronically infected with HCV and are at risk of developing serious liver disease. Despite the advent of effective antiviral therapy, the frequency of chronic carriers has only marginally decreased. A major roadblock in developing a vaccine that would prevent transmission is the scarcity of animal models that are susceptible to HCV infection. It is poorly understood why HCV infects only humans and chimpanzees. To develop an animal model for hepatitis C, previous efforts focused on modifying the host environment of mice, for example, to render them more susceptible to HCV infection. Here, we attempted a complementary approach in which a laboratory-derived HCV variant was tested for its ability to infect mice. We demonstrate that this engineered HCV strain can enter mouse liver cells but does not replicate efficiently. Thus, additional adaptations are likely needed to construct a robust animal model for HCV.

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P111: Viral adaptation approaches to adapt hepatitis C virus to the murine host

Journal of Viral Hepatitis ◽

10.1111/jvh.105_12425 ◽

2015 ◽

Vol 22 ◽

pp. 76-77

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Viral Adaptation

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Barriers to hepatitis C virus elimination in MSM living with HIV: The high risk of reinfection. Case study: A patient with 6 episodes

Gastroenterología y Hepatología (English Edition) ◽

10.1016/j.gastre.2019.04.005 ◽

2019 ◽

Vol 42 (9) ◽

pp. 555-556

Author(s):

Montserrat Laguno ◽

Maria Martínez-Rebollar ◽

Lorena de la Mora ◽

Sofía Pérez-del-Pulgar ◽

Josep Mallolas

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

High Risk ◽

Virus Elimination ◽

Living With Hiv

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Challenges in Modern Drug Discovery: A Case Study of Boceprevir, an HCV Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Accounts of Chemical Research ◽

10.1021/ar700109k ◽

2008 ◽

Vol 41 (1) ◽

pp. 50-59 ◽

Cited By ~ 156

Author(s):

F. George Njoroge ◽

Kevin X. Chen ◽

Neng-Yang Shih ◽

John J. Piwinski

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Drug Discovery ◽

Virus Infection ◽

Protease Inhibitor ◽

Hepatitis C Virus Infection ◽

Modern Drug ◽

Hcv Protease

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A case study of the application of WEKA software to solve the problem of liver inflamation

10.21203/rs.3.rs-464435/v1 ◽

2021 ◽

Author(s):

Željko Vujović

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Binary Classification ◽

Software Tool ◽

Data Set ◽

A Value ◽

Egyptian Patients ◽

Sensitivity Specificity ◽

Fold Cross Validation

Abstract The aim of this paper was to consider the reliability of the basic metrics of evaluation of classification models: accuracy, sensitivity, specificity and precision. The WEKA software tool was applied to the "Hepatitis C virus (HCV) for Egyptian patients dataset". The algorithms Bayesnet, Naivebayesh, Multilayer Perceptron, J48 and 10-fold cross validation were used in the study. The main results obtained are that, with all four algorithms in question, they achieved approximately the same accuracy of correctly classified specimens. BaiesNet - 22.96%, NaiveBaies - 26.14%, MultilaierPerceptron - 26.57% and J48 - 25.27%. Binary classification metrics - sensitivity, specificity and precision show very different values, depending on the intended class. Metric specificity, for all four algorithms, shows that a value that is in most of the range of possible values [0,1]. Metric sensitivity and precision, for all four algorithms, showed values that are in the lower part of the range of possible values [0,1]. The results of this study showed that WEKA software could not yet be considered as a relevant tool for the diagnosis of Hepatitis C Virus, on whose data set it was applied.

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Hepatitis C Virus Adaptation to T-Cell Immune Pressure

The Scientific World JOURNAL ◽

10.1155/2013/673240 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

A. Plauzolles ◽

M. Lucas ◽

S. Gaudieri

Keyword(s):

Immune Response ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Host Factors ◽

Cell Immune Response ◽

Viral Diversity ◽

Immune Pressure ◽

Viral Adaptation ◽

Virus Adaptation

Replication of the hepatitis C virus (HCV) is an error-prone process. This high error rate results in the emergence of viral populations (quasispecies) within hosts and contributes to interhost variability. Numerous studies have demonstrated that both viral and host factors contribute to this viral diversity, which can ultimately affect disease outcome. As the host’s immune response is an important correlate of infection outcome for HCV, many of these viral variations are strongly influenced by T-cell immune pressure and accordingly constitute an efficient strategy to subvert such pressures (viral adaptations). This paper will review the data on viral diversity observed between and within hosts infected with HCV from the acute to the chronic stage of infection and will focus on viral adaptation to the host’s T-cell immune response.

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