Host range studies of GB virus-B hepatitis agent, the closest relative of hepatitis C virus, in New World monkeys and chimpanzees

2001 ◽  
Vol 65 (4) ◽  
pp. 694-697 ◽  
Author(s):  
Jens Bukh ◽  
Carl L. Apgar ◽  
Sugantha Govindarajan ◽  
Robert H. Purcell
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Range ◽  
New World ◽  
New World Monkeys

scholarly journals Unexpected host range of hepatitis C virus replicons

Hepatology ◽  
2004 ◽  
Vol 39 (3) ◽  
pp. 835-838 ◽  
Author(s):  
Ralf Bartenschlager
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Range

scholarly journals Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Qiang Ding ◽  
Markus von Schaewen ◽  
Gabriela Hrebikova ◽  
Brigitte Heller ◽  
Lisa Sandmann ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Range ◽  
Amino Acid Sequences ◽  
Host Factors ◽  
Narrow Host Range ◽  
Junction Protein ◽  
Mouse Hepatocytes

ABSTRACT Hepatitis C virus (HCV) causes chronic infections in at least 150 million individuals worldwide. HCV has a narrow host range and robustly infects only humans and chimpanzees. The underlying mechanisms for this narrow host range are incompletely understood. At the level of entry, differences in the amino acid sequences between the human and mouse orthologues of two essential host factors, the tetraspanin CD81 and the tight junction protein occludin (OCLN), explain, at least in part, HCV's limited ability to enter mouse hepatocytes. We have previously shown that adenoviral or transgenic overexpression of human CD81 and OCLN facilitates HCV uptake into mouse hepatocytes in vitro and in vivo. In efforts to refine these models, we constructed knock-in mice in which the second extracellular loops of CD81 and OCLN were replaced with the respective human sequences, which contain the determinants that are critical for HCV uptake. We demonstrate that the humanized CD81 and OCLN were expressed at physiological levels in a tissue-appropriate fashion. Mice bearing the humanized alleles formed normal tight junctions and did not exhibit any immunologic abnormalities, indicating that interactions with their physiological ligands were intact. HCV entry factor knock-in mice take up HCV with an efficiency similar to that in mice expressing HCV entry factors transgenically or adenovirally, demonstrating the utility of this model for studying HCV infection in vivo. IMPORTANCE At least 150 million individuals are chronically infected with hepatitis C virus (HCV). Chronic hepatitis C can result in progressive liver disease and liver cancer. New antiviral treatments can cure HCV in the majority of patients, but a vaccine remains elusive. To gain a better understanding of the processes culminating in liver failure and cancer and to prioritize vaccine candidates more efficiently, small-animal models are needed. Here, we describe the characterization of a new mouse model in which the parts of two host factors that are essential for HCV uptake, CD81 and occludin (OCLN), which differ between mice and humans, were humanized. We demonstrate that such minimally humanized mice develop normally, express the modified genes at physiological levels, and support HCV uptake. This model is of considerable utility for studying viral entry in the three-dimensional context of the liver and to test approaches aimed at preventing HCV entry.

scholarly journals A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B

2008 ◽  
Vol 89 (8) ◽  
pp. 1911-1920 ◽  
Author(s):  
Jamel Mankouri ◽  
Andrew Milward ◽  
Kenneth R. Pryde ◽  
Lucile Warter ◽  
Annette Martin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Signalling ◽  
Pi3k Pathway ◽  
Luciferase Reporter ◽  
Signalling Pathways ◽  
New World Monkeys ◽  
Structural Protein ◽  
Reporter System ◽  
Early Endosomes

GB virus B (GBV-B) is the closest relative to hepatitis C virus (HCV) with which it shares a common genome organization, however, unlike HCV in humans, it generally causes an acute resolving hepatitis in New World monkeys. It is important to understand the factors regulating the different disease profiles of the two viruses and in this regard, as well as playing a key role in viral RNA replication, the HCV NS5A non-structural protein modulates a variety of host-cell signalling pathways. We have shown previously that HCV NS5A, expressed either alone, or in the context of the complete polyprotein, inhibits the Ras-extracellular-signal-regulated kinase (Erk) pathway and activates the phosphoinositide 3-kinase (PI3K) pathway. In this report, we investigate whether these functions are shared by GBV-B NS5A. Immunofluorescence analysis revealed that a C-terminally FLAG-tagged GBV-B NS5A exhibited a punctate cytoplasmic distribution. However, unlike HCV NS5A, the GBV-B protein did not partially co-localize with early endosomes. Utilizing a transient luciferase reporter system, we observed that GBV-B NS5A failed to inhibit Ras–Erk signalling, however GBV-B NS5A expression did result in the elevation of β-catenin-dependent transcription via activation of the PI3K pathway. These effects of GBV-B and HCV NS5A on the PI3K and Ras–Erk pathways were confirmed in cells harbouring subgenomic replicons derived from the two viruses. Based on these data we speculate that the differential effects of the two NS5A proteins on cellular signalling pathways may contribute to the differences in the natural history of the two viruses.

scholarly journals Determinants Involved in Hepatitis C Virus and GB Virus B Primate Host Restriction

2015 ◽  
Vol 89 (23) ◽  
pp. 12131-12144 ◽  
Author(s):  
Caroline Marnata ◽  
Aure Saulnier ◽  
Dimitri Mompelat ◽  
Thomas Krey ◽  
Lisette Cohen ◽  
...  
Keyword(s):  
Cell Culture ◽  
Life Cycle ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
New World ◽  
Progeny Virus ◽  
New World Primates ◽  
Primate Model ◽  
Adaptive Mutations ◽  
Hepatocyte Cultures

ABSTRACTHepatitis C virus (HCV) only infects humans and chimpanzees, while GB virus B (GBV-B), another hepatotropic hepacivirus, infects small New World primates (tamarins and marmosets). In an effort to develop an immunocompetent small primate model for HCV infection to study HCV pathogenesis and vaccine approaches, we investigated the HCV life cycle step(s) that may be restricted in small primate hepatocytes. First, we found that replication-competent, genome-length chimeric HCV RNAs encoding GBV-B structural proteins in place of equivalent HCV sequences designed to allow entry into simian hepatocytes failed to induce viremia in tamarins following intrahepatic inoculation, nor did they lead to progeny virus in permissive, transfected human Huh7.5 hepatoma cells upon serial passage. This likely reflected the disruption of interactions between distantly related structural and nonstructural proteins that are essential for virion production, whereas such cross talk could be restored in similarly designed HCV intergenotypic recombinants via adaptive mutations in NS3 protease or helicase domains. Next, HCV entry into small primate hepatocytes was examined directly using HCV-pseudotyped retroviral particles (HCV-pp). HCV-pp efficiently infected tamarin hepatic cell lines and primary marmoset hepatocyte cultures through the use of the simian CD81 ortholog as a coreceptor, indicating that HCV entry is not restricted in small New World primate hepatocytes. Furthermore, we observed genomic replication and modest virus secretion following infection of primary marmoset hepatocyte cultures with a highly cell culture-adapted HCV strain. Thus, HCV can successfully complete its life cycle in primary simian hepatocytes, suggesting the possibility of adapting some HCV strains to small primate hosts.IMPORTANCEHepatitis C virus (HCV) is an important human pathogen that infects over 150 million individuals worldwide and leads to chronic liver disease. The lack of a small animal model for this infection impedes the development of a preventive vaccine and pathogenesis studies. In seeking to establish a small primate model for HCV, we first attempted to generate recombinants between HCV and GB virus B (GBV-B), a hepacivirus that infects small New World primates (tamarins and marmosets). This approach revealed that the genetic distance between these hepaciviruses likely prevented virus morphogenesis. We next showed that HCV pseudoparticles were able to infect tamarin or marmoset hepatocytes efficiently, demonstrating that there was no restriction in HCV entry into these simian cells. Furthermore, we found that a highly cell culture-adapted HCV strain was able to achieve a complete viral cycle in primary marmoset hepatocyte cultures, providing a promising basis for further HCV adaptation to small primate hosts.

scholarly journals DNA Polymerase Sequences of New World Monkey Cytomegaloviruses: Another Molecular Marker with Which To Infer Platyrrhini Systematics

2018 ◽  
Vol 92 (18) ◽  
Author(s):  
Samantha James ◽  
Damien Donato ◽  
Jean-François Pouliquen ◽  
Manuel Ruiz-García ◽  
Anne Lavergne ◽  
...  
Keyword(s):  
Amino Acid ◽  
Host Range ◽  
Dna Polymerase ◽  
New World ◽  
Phylogenetic Analyses ◽  
Primate Species ◽  
New World Monkeys ◽  
Polymerase Gene ◽  
Evolutionary Processes ◽  
Genus Level

ABSTRACTOver the past few decades, a large number of studies have identified herpesvirus sequences from many mammalian species around the world. Among the different nonhuman primate species tested so far for cytomegaloviruses (CMVs), only a few were from the New World. Seeking to identify CMV homologues in New World monkeys (NWMs), we carried out molecular screening of 244 blood DNA samples from 20 NWM species from Central and South America. Our aim was to reach a better understanding of their evolutionary processes within the Platyrrhini parvorder. Using PCR amplification with degenerate consensus primers targeting highly conserved amino acid motifs encoded by the herpesvirus DNA polymerase gene, we characterized novel viral sequences from 12 species belonging to seven genera representative of the three NWM families. BLAST searches, pairwise nucleotide and amino acid sequence comparisons, and phylogenetic analyses confirmed that they all belonged to theCytomegalovirusgenus. Previously determined host taxa allowed us to demonstrate a good correlation between the distinct monophyletic clades of viruses and those of the infected primates at the genus level. In addition, the evolutionary branching points that separate NWM CMVs were congruent with the divergence dates of their hosts at the genus level. These results significantly expand our knowledge of the host range of this viral genus and strongly support the occurrence of cospeciation between these viruses and their hosts. In this respect, we propose that NWM CMV DNA polymerase gene sequences may serve as reliable molecular markers with which to infer Platyrrhini phylogenetics.IMPORTANCEInvestigating evolutionary processes between viruses and nonhuman primates has led to the discovery of a large number of herpesviruses. No study published so far on primate cytomegaloviruses has extensively studied New World monkeys (NWMs) at the subspecies, species, genus, and family levels. The present study sought to identify cytomegalovirus homologues in NWMs and to decipher their evolutionary relationships. This led us to characterize novel viruses from 12 of the 20 primate species tested, which are representative of the three NWM families. The identification of distinct viruses in these primates not only significantly expands our knowledge of the host range of this viral genus but also sheds light on its evolutionary history. Phylogenetic analyses and molecular dating of the sequences obtained support a virus-host coevolution.

scholarly journals Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus

Hepatology ◽  
2005 ◽  
Vol 41 (2) ◽  
pp. 265-274 ◽  
Author(s):  
Dimitri Lavillette ◽  
Alexander W. Tarr ◽  
C�cile Voisset ◽  
Peggy Donot ◽  
Birke Bartosch ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Range ◽  
Cell Entry

scholarly journals Persistent replication of a hepatitis C virus genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B in a New World monkey

2016 ◽  
Vol 60 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Saori Suzuki ◽  
Ken-ichi Mori ◽  
Atsunori Higashino ◽  
Yuki Iwasaki ◽  
Yasuhiro Yasutomi ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
New World ◽  
World Monkey ◽  
Virus Genotype ◽  
New World Monkey ◽  
Chimeric Clone ◽  
Genotype 1B
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