Cell culture-adaptive mutations in hepatitis C virus promote viral production by enhancing viral replication and release

Wang, Qi; Li, Yue; Liu, Shun-Ai; Xie, Wen; Cheng, Jun

doi:10.3748/wjg.v24.i12.1299

Cited by 5 publications

(3 citation statements)

References 54 publications

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“…3B, C). This was unexpected as this chimera includes a previously described titer enhancing mutation in NS5A, C2274R [46, 47]. However, we also identified V2440M in NS5A as a second adaptive mutation in NS5A.…”

Section: Discussionmentioning

confidence: 58%

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Hepatitis C virus cell culture adaptive mutations enhance cell culture propagation by multiple mechanisms but boost antiviral responses in primary human hepatocytes

Frericks,

Brown,

Reinecke

et al. 2023

Preprint

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Hepatitis C virus (HCV) infection progresses to chronicity in the majority of infected individuals. Its high intra-host genetic variability enables HCV to evade the continuous selection pressure exerted by the host, contributing to persistent infection. Utilizing a cell culture adapted HCV population (p100pop) which exhibits increased replicative capacity in various liver cell lines, this study investigated virus and host determinants which underlie enhanced viral fitness. Characterization of a panel of molecular p100 clones revealed that cell culture adaptive mutations optimize a range of virus-host interactions, resulting in expanded cell tropism, altered dependence on the cellular co-factor micro-RNA 122 and increased rates of virus spread. On the host side, comparative transcriptional profiling of hepatoma cells infected either with p100pop or its progenitor virus revealed that enhanced replicative fitness correlated with activation of endoplasmic reticulum stress signaling and the unfolded protein response. In contrast, infection of primary human hepatocytes with p100pop led to a mild attenuation of virion production which correlated with a greater induction of cell-intrinsic antiviral defense responses. In summary, long-term passage experiments in cells where selective pressure from innate immunity is lacking improves multiple virus-host interactions, enhancing HCV replicative fitness. However, this study further indicates that HCV has evolved to replicate at low levels in primary human hepatocytes to minimize innate immune activation, highlighting that an optimal balance between replicative fitness and innate immune induction is key to establishing persistence.Author SummaryHCV infection remains a global health burden with 58 million people currently chronically infected. However, the detailed molecular mechanisms which underly persistence are incompletely defined. We utilized a long-term cell culture adapted HCV, exhibiting enhanced replicative fitness in different human liver cell lines, in order to identify molecular principles by which HCV optimizes its replication fitness. Our experimental data revealed that cell culture adaptive mutations confer changes in the host response and usage of various host factors. The latter allows functional flexibility at different stages of the viral replication cycle. However, increased replicative fitness resulted in an increased activation of the innate immune system, which likely poses boundary for functional variation in authentic hepatocytes, explaining the observed attenuation of the adapted virus population in primary hepatocytes.

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Section: Discussionmentioning

confidence: 58%

“…3B, C). This was unexpected as this chimera includes a previously described titer enhancing mutation in NS5A, C2274R [46,47].…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus cell culture adaptive mutations enhance cell culture propagation by multiple mechanisms but boost antiviral responses in primary human hepatocytes

Frericks,

Brown,

Reinecke

et al. 2023

Preprint

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show abstract

“…The use of live-attenuated whole virus particles is a common strategy for vaccine development. However, in the case of HCV, the feasibility of live vaccines is uncertain, as in vitro-grown strains of HCV have a high rate of adaptive mutation, which eventually leads to the generation of highly efficient replicative strains [92][93][94]. However, for unknown reasons, the infectivity of such strains in primate cell lines and primate animal models is very low [95][96][97].…”

Section: Challenges In Vaccine Designmentioning

confidence: 99%

Progress, evolving therapeutic/diagnostic approaches, and challenges in the management of hepatitis C virus infections

2022

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Hepatitis C virus (HCV) infections are emerging as one of the foremost challenges in healthcare owing to its chronicity and the virus's quasispecies nature. Worldwide, over 170 million people are chronically infected with HCV, with an annual mortality of over 500,000 people across the world. The emerging pathophysiological evidence links HCV infections to a risk of developing liver diseases such as cirrhosis and hepatocellular carcinoma. Despite the great strides that have been made towards understanding the pathophysiology of disease progression, the tailored treatments of HCV infection remain to be established. The present review provides an update of the literature pertaining to evolving therapeutic approaches and prophylactic measures for the effective management of HCV infections. An extensive discussion of established and experimental immune prophylactic measures also sheds light on current developments in the design of vaccination strategies against HCV infection. We have also attempted to address the application of nanotechnology in formulating effective therapeutic interventions against HCV. Pointing out the limitations of the existing diagnostic methods and therapeutic approaches against HCV might inspire the design and development of novel, efficient, reliable, and cost-effective diagnostic technologies as well as novel therapeutic and immune prophylactic interventions for the effective management of HCV.

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Current status and future development of infectious cell-culture models for the major genotypes of hepatitis C virus: Essential tools in testing of antivirals and emerging vaccine strategies

Ramírez

Bukh

2018

Antiviral Research

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Cell culture-adaptive mutations in hepatitis C virus promote viral production by enhancing viral replication and release

Cited by 5 publications

References 54 publications

Hepatitis C virus cell culture adaptive mutations enhance cell culture propagation by multiple mechanisms but boost antiviral responses in primary human hepatocytes

Hepatitis C virus cell culture adaptive mutations enhance cell culture propagation by multiple mechanisms but boost antiviral responses in primary human hepatocytes

Progress, evolving therapeutic/diagnostic approaches, and challenges in the management of hepatitis C virus infections

Current status and future development of infectious cell-culture models for the major genotypes of hepatitis C virus: Essential tools in testing of antivirals and emerging vaccine strategies

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