The elusive function of the hepatitis C virus p7 protein

Atoom, Ali M.; Taylor, Nathan; Russell, Rodney S.

doi:10.1016/j.virol.2014.04.018

Cited by 38 publications

(21 citation statements)

References 111 publications

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“…This hypothesis is supported by the fact that intracellular pH has been described to regulate protein binding and targeting to certain lipids (54). Alternatively, the C766Y amino acid change could directly increase ER-lipid droplet contacts through yet-unknown membrane-protein interactions via the p7 transmembrane domain (55). The C766Y culture-adapted mutation in p7 on its own does not substantially increase viral titer.…”

Section: Discussionmentioning

confidence: 99%

Cooperation between the Hepatitis C Virus p7 and NS5B Proteins Enhances Virion Infectivity

Aligeti

Roder

Horner

2015

J Virol

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The molecular mechanisms that govern hepatitis C virus (HCV) assembly, release, and infectivity are still not yet fully understood. In the present study, we sequenced a genotype 2A strain of HCV (JFH-1) that had been cell culture adapted in Huh-7.5 cells to produce nearly 100-fold-higher viral titers than the parental strain. Sequence analysis identified nine mutations in the genome, present within both the structural and nonstructural genes. The infectious clone of this virus containing all nine culture-adapted mutations had 10-fold-higher levels of RNA replication and RNA release into the supernatant but had nearly 1,000-fold-higher viral titers, resulting in an increased specific infectivity compared to wild-type JFH-1. Two mutations, identified in the p7 polypeptide and NS5B RNA-dependent RNA polymerase, were sufficient to increase the specific infectivity of JFH-1. We found that the culture-adapted mutation in p7 promoted an increase in the size of cellular lipid droplets following transfection of viral RNA. In addition, we found that the culture-adaptive mutations in p7 and NS5B acted synergistically to enhance the specific viral infectivity of JFH-1 by decreasing the level of sphingomyelin in the virion. Overall, these results reveal a genetic interaction between p7 and NS5B that contributes to virion specific infectivity. Furthermore, our results demonstrate a novel role for the RNA-dependent RNA polymerase NS5B in HCV assembly. IMPORTANCEHepatitis C virus assembly and release depend on viral interactions with host lipid metabolic pathways. Here, we demonstrate that the viral p7 and NS5B proteins cooperate to promote virion infectivity by decreasing sphingomyelin content in the virion. Our data uncover a new role for the viral RNA-dependent RNA polymerase NS5B and p7 proteins in contributing to virion morphogenesis. Overall, these findings are significant because they reveal a genetic interaction between p7 and NS5B, as well as an interaction with sphingomyelin that regulates virion infectivity. Our data provide new strategies for targeting host lipid-virus interactions as potential targets for therapies against HCV infection. Hepatitis C virus (HCV), a positive-sense single-stranded RNA virus and a member of the Flaviviridae family, infects nearly 170 million people worldwide (1, 2). HCV infection is the leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (3). While the previous interferon-based therapies for treatment of hepatitis C were effective in only 40% of those infected with genotype 1 virus, the most prevalent HCV genotype in the United States (4), newly developed therapies for hepatitis C now use interferon-free direct-acting antiviral (DAA) regimens, with over 90% success rates (5). However, antiviral resistance is still a problem, and a vaccine is not yet available for prevention of HCV transmission.The HCV RNA genome is translated into a single polyprotein from an internal ribosome entry site located in the 5= untranslated region of the genome. The resu...

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Section: Discussionmentioning

confidence: 99%

Cooperation between the Hepatitis C Virus p7 and NS5B Proteins Enhances Virion Infectivity

Aligeti

Roder

Horner

2015

J Virol

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“…A single polyprotein is translated from its genome and is processed by HCV-encoding proteases such as HCV NS2 cysteine protease and HCV NS3/4A serine protease as well as host transpeptidases, into four structural (core, E1, E2 and p7) and six nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins [ 3 ]. However, opinions may differ regarding p7, as the function of p7 is uncertain [ 17 , 18 ]. The HCV RNA replication complex develops in the endoplasmic reticulum, where HCV replication occurs.…”

Section: Hcv Genome and Its Coding Proteinsmentioning

confidence: 99%

Faldaprevir for the Treatment of Hepatitis C

Yokosuka

Omata

2015

IJMS

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The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new generation of HCV NS3/4A protease inhibitors. At the end of 2013, the US Food and Drug Administration (FDA) approved the HCV NS3/4A protease inhibitor simeprevir and the HCV NS5B polymerase inhibitor sofosbuvir. Simeprevir or sofosbuvir in combination with pegylated interferon and ribavirin are available for clinical use. Faldaprevir, another HCV NS3/4A protease inhibitor that also has fewer adverse events than telaprevir or boceprevir, is under development. Of interest, faldaprevir in combination with pegylated interferon and ribavirin, and interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin provides high sustained virological response rates for HCV genotype 1 infection. The aim of this article is to review these data concerning faldaprevir. Faldaprevir in combination with pegylated interferon and ribavirin treatment appears to be associated with fewer adverse events than telaprevir or boceprevir in combination with pegylated interferon and ribavirin, and may be one of the therapeutic options for treatment-naive patients with HCV genotype 1. The interferon-free combination of faldaprevir and deleobuvir with ribavirin was effective for HCV genotype 1 infection and may hold promise for interferon-ineligible and interferon-intolerant patients.

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“…Furthermore, substitution of p7 with the influenza A virus M2 proton channel, human immunodeficiency virus type 1 Vpu, or the acidification inhibitor bafilomycin A1 is not sufficient to rescue p7 function and release infectious particles in the absence of functional p7 [23,24]. These results suggest the possibility of an unidentified function of p7 independent of ion channel activity and its role in capsid envelopment [23][24][25]. In this study, we explore another ion channel-independent role of p7 in inducing lipid raft adhesion.…”

Section: Introductionmentioning

confidence: 95%

Hepatitis C virus p7 mediates membrane-to-membrane adhesion

Lee

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The elusive function of the hepatitis C virus p7 protein

Cited by 38 publications

References 111 publications

Cooperation between the Hepatitis C Virus p7 and NS5B Proteins Enhances Virion Infectivity

Cooperation between the Hepatitis C Virus p7 and NS5B Proteins Enhances Virion Infectivity

Faldaprevir for the Treatment of Hepatitis C

Hepatitis C virus p7 mediates membrane-to-membrane adhesion

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