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1.  Bile Acids Promote HCV Replication through the EGFR/ERK Pathway in Replicon-Harboring Cells 
Intervirology  2011;54(6):339-348.
Objectives
Bile acids promoted the replication of hepatitis C virus (HCV) and compromised the anti-HCV effects of interferon-α (IFN-α) in replicon-harboring cells. To explore a potential mechanism for the observation, we studied the effects of bile acids on the epidermal growth factor receptor (EGFR) and the extracellular signal-regulated kinase (ERK) pathway in association with HCV replication in genotype 1a or 1b replicon-harboring cells.
Methods
Replicon-harboring cells were treated with various bile acids, IFN-α and small molecule inhibitors either individually or combined together. The effects of these treatments were measured using cell cycle analysis, qRT-PCR, and Western blot analysis.
Results
Bile acids induced the activation of EGFR/ERK pathway and extended S-phase of cells, which was correlated with the increased levels of viral replication. The inhibitors of EGFR (AG1478) or ERK (U0126) significantly mitigated the bile acid-mediated promotion of HCV replication. When AG1478 or U0126 were added to the treatment of bile acids and IFN-α, they were able to restore the anti-HCV effects of IFN-α.
Conclusion
Our data suggest that the addition of an EGFR or ERK inhibitor to the current IFN-α-based regimen may improve overall treatment efficacy by blocking the bile acid-mediated promotion of HCV replication.
doi:10.1159/000321452
PMCID: PMC3214831  PMID: 21293096
Bile acids; EGFR/ERK pathway; Hepatitis C virus; HCV replication; Replicon-harboring cells
2.  The Three-Dimensional Structure of Mimivirus 
Intervirology  2010;53(5):268-273.
Mimivirus, the prototypic member of the new family of Mimiviridae, is the largest virus known to date. Progress has been made recently in determining the three-dimensional structure of the 0.75-μm diameter virion using cryo-electron microscopy and atomic force microscopy. These showed that the virus is composed of an outer layer of dense fibers surrounding an icosahedrally shaped capsid and an internal membrane sac enveloping the genomic material of the virus. Additionally, a unique starfish-like structure at one of the fivefold vertices, required by the virus for infecting its host, has been defined in more detail.
doi:10.1159/000312911
PMCID: PMC2895761  PMID: 20551678
Atomic force microscopy; Cryo-electron microscopy; Mimivirus, three-dimensional structure; Nucleocytoplasmic large DNA viruses
3.  Origin and Evolution of Eukaryotic Large Nucleo-Cytoplasmic DNA Viruses 
Intervirology  2010;53(5):284-292.
Background/Aims
The nucleo-cytoplasmic large DNA viruses (NCLDV) constitute an apparently monophyletic group that consists of 6 families of viruses infecting a broad variety of eukaryotes. A comprehensive genome comparison and maximum-likelihood reconstruction of NCLDV evolution reveal a set of approximately 50 conserved genes that can be tentatively mapped to the genome of the common ancestor of this class of eukaryotic viruses. We address the origins and evolution of NCLDV.
Results
Phylogenetic analysis indicates that some of the major clades of NCLDV infect diverse animals and protists, suggestive of early radiation of the NCLDV, possibly concomitant with eukaryogenesis. The core NCLDV genes seem to have originated from different sources including homologous genes of bacteriophages, bacteria and eukaryotes. These observations are compatible with a scenario of the origin of the NCLDV at an early stage of the evolution of eukaryotes through extensive mixing of genes from widely different genomes.
Conclusions
The common ancestor of the NCLDV probably evolved from a bacteriophage as a result of recruitment of numerous eukaryotic and some bacterial genes, and concomitant loss of the majority of phage genes except for a small core of genes coding for proteins essential for virus genome replication and virion formation.
doi:10.1159/000312913
PMCID: PMC2895762  PMID: 20551680
Bacteriophage; Eukaryogenesis; Nucleo-cytoplasmic large DNA viruses, evolution; Phylogenetic analysis
4.  Epstein-Barr Virus WZhet DNA Can Induce Lytic Replication in Epithelial Cells in vitro, although WZhet Is Not Detectable in Many Human Tissues in vivo 
Intervirology  2009;52(1):8-16.
Objective
WZhet is a rearranged and partially deleted form of the Epstein-Barr virus (EBV) genome in which the BamH1W region becomes juxtaposed with and activates BZLF1, resulting in constitutive viral replication. We tested whether WZhet induces viral replication in epithelial cells, and we studied its prevalence in a wide range of lesional tissues arising in vivo.
Methods
A quantitative real-time PCR assay targeting EBV WZhet DNA was developed to measure this recombinant form of the EBV genome.
Results
WZhet DNA was undetectable in any of 324 plasma or paraffin-embedded tissue samples from patients with EBV-associated and EBV-negative disorders. These included specimens from patients with Hodgkin or non-Hodgkin lymphoma, post-transplant lymphoproliferation, nasopharyngeal or gastric adenocarcinoma, and infectious mononucleosis. However, WZhet DNA was detected in vitro in EBV-infected AGS gastric cancer cells. Additionally, transient transfection of infected AGS gastric cancer cells showed that viral replication could be induced by a WZhet plasmid.
Conclusion
This is the first evidence that WZhet induces the EBV lytic cycle in an epithelial cell line. Our negative findings in natural settings suggest that WZhet is a defective viral product that thrives in the absence of a host immune system but is rarely present in vivo.
doi:10.1159/000210833
PMCID: PMC2865398  PMID: 19349713
Epstein-Barr virus; WZhet; Recombination; Lymphoma; Carcinoma; Replication; Viral load
5.  Proviral Loads and Clonal Expansion of HTLV-1-Infected Cells following Vertical Transmission: A 10-Year Follow-Up of Children in Jamaica 
Intervirology  2009;52(3):115-122.
Objective
Few studies have specifically examined proviral load (PVL) and clonal evolution of human T-lymphotropic virus type 1 (HTLV-1)-infected cells in vertically infected children.
Methods
Sequential samples (from ages 1 to 16 years) from 3 HTLV-1-infected children (cases A, B and C) in the Jamaica Mother Infant Cohort Study were analyzed for their PVL and clonal expansion of HTLV-1-infected cells in peripheral blood mononuclear cells (PBMCs) by inverse-long PCR.
Results
The baseline PVL (per 100,000 PBMCs) of case A was 260 (at 1 year of age) and of case B it was 1,867 (at 3 years of age), and they remained constant for more than 10 years. Stochastic patterns of clonal expansion of HTLV-1-infected cells were predominately detected. In contrast, case C, who had lymphadenopathy, seborrheic dermatitis and hyperreflexia, showed an increase in PVL from 2,819 at 1.9 years to 13,358 at 13 years of age, and expansion of 2 dominant clones.
Conclusion
The clonal expansion of HTLV-1-infected cells is induced in early childhood after infection acquired from their mothers. Youths with high PVL and any signs and symptoms associated with HTLV-1 infection should be closely monitored.
doi:10.1159/000219384
PMCID: PMC2790750  PMID: 19468234
HTLV-1 infection; Clonal expansion, infected cells; Transmission, vertical

Results 1-5 (5)