Abstract:
:The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor- and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.
journal_name
J Viroljournal_title
Journal of virologyauthors
Nyanguile O,Devogelaere B,Vijgen L,Van den Broeck W,Pauwels F,Cummings MD,De Bondt HL,Vos AM,Berke JM,Lenz O,Vandercruyssen G,Vermeiren K,Mostmans W,Dehertogh P,Delouvroy F,Vendeville S,VanDyck K,Dockx K,Cleiren E,Rdoi
10.1128/JVI.01980-09subject
Has Abstractpub_date
2010-03-01 00:00:00pages
2923-34issue
6eissn
0022-538Xissn
1098-5514pii
JVI.01980-09journal_volume
84pub_type
杂志文章abstract::Cytoplasmic virus-specific RNA and polyribosomes from a chronically infected feline thymus tumor cell line, F-422, were analyzed by using in vitro-synthesized feline leukemia virus (Rickard strain) (R-FeLV) complementary DNA (cDNA) probe. By hybridization kinetics analysis, cytoplasmic, polyribosomat, and nuclear RNAs...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.25.3.750-763.1978
更新日期:1978-03-01 00:00:00
abstract::To assess the heterogeneity of cytotoxic T lymphocytes (CTLs) directed against viral epitopes, we studied six class I major histocompatibility complex-restricted (H-2Db) CTL clones that recognize the same 9-amino-acid immunodominant epitope, amino acids 278 to 286 from envelope glycoprotein 2 (GP2) of lymphocytic chor...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.5.1845-1851.1989
更新日期:1989-05-01 00:00:00
abstract::Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4⁺-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.05609-11
更新日期:2012-01-01 00:00:00
abstract::The replication of many positive-strand RNA viruses [(+)RNA viruses] depends on the cellular protein GBF1, but its role in the replication process is not clear. In uninfected cells, GBF1 activates small GTPases of the Arf family and coordinates multiple steps of membrane metabolism, including functioning of the cellul...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00856-19
更新日期:2019-10-15 00:00:00
abstract::Marek's disease virus DNA appears to be wound around a central structure connecting the two inner poles of the capsid. Based on electron micrographs of Marek's disease virions, a diagram of spatial configuration of virus DNA is presented. This diagram may explain the pleomorphic character of the herpesvirus core obser...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.13.5.1148-1150.1974
更新日期:1974-05-01 00:00:00
abstract::We previously showed that the cellular proteins ZEB1 and ZEB2/SIP1 both play key roles in regulating the latent-lytic switch of Epstein-Barr Virus (EBV) by repressing BZLF1 gene expression. We investigated here the effects of cellular microRNA (miRNA) 200 (miR200) family members on the EBV infection status of cells. W...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00923-10
更新日期:2010-10-01 00:00:00
abstract::A panel of monoclonal antibodies that recognize the two major glycoproteins of bovine viral diarrhea virus (BDV) was used to evaluate the antigenic relationship between cytopathic (CP) and noncytopathic (NCP) viruses isolated from cattle dead or dying from fatal BDV infections. Various unrelated BDV isolates were init...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.62.8.2823-2827.1988
更新日期:1988-08-01 00:00:00
abstract::Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a transmissible lung cancer of sheep known as ovine pulmonary carcinoma. Recently, we have found that the expression of the JSRV envelope (Env) is sufficient to transform mouse NIH 3T3 cells in classical transformation assays. To further investigate the mech...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.22.11002-11009.2001
更新日期:2001-11-01 00:00:00
abstract::The coding capacity of human cytomegalovirus (HCMV) for glycoproteins by far exceeds that of other herpesviruses. Few of these proteins have been characterized so far. We have investigated the gene product of reading frame UL132. The putative protein product of UL132 is a glycoprotein with a theoretical mass of 29.8 k...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.18.11837-11847.2005
更新日期:2005-09-01 00:00:00
abstract::High-risk human papillomavirus type 16 (HPV16) is the primary causative agent of cervical cancer and therefore is responsible for significant morbidity and mortality worldwide. Cellular transformation is mediated directly by the expression of viral oncogenes, the least characterized of which, E5, subverts cellular pro...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.06243-11
更新日期:2012-05-01 00:00:00
abstract::The extracellular virion form (EV) of vaccinia virus (VACV) is essential for viral pathogenesis and is difficult to neutralize with antibodies. Why this is the case and how the smallpox vaccine overcomes this challenge remain incompletely understood. We previously showed that high concentrations of anti-B5 antibodies ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02152-12
更新日期:2013-02-01 00:00:00
abstract::Passage of native classical swine fever virus (CSFV) in cultured swine kidney cells (SK6 cells) selects virus variants that attach to the surface of cells by interaction with membrane-associated heparan sulfate (HS). A Ser-to-Arg change in the C terminus of envelope glycoprotein E(rns) (amino acid 476 in the open read...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.20.9585-9595.2001
更新日期:2001-10-01 00:00:00
abstract::The sheep genome harbors approximately 20 endogenous retroviruses (enJSRVs) highly related to the exogenous Jaagsiekte sheep retrovirus (JSRV). One of the enJSRV loci, enJS56A1, acts as a unique restriction factor by blocking JSRV in a transdominant fashion at a late stage of the retroviral cycle. To better understand...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01859-06
更新日期:2007-02-01 00:00:00
abstract::The Duplan strain of murine leukemia virus induces murine AIDS in C57BL/6 mice. When spleen cells from C57BL/6 mice infected with the virus were transplanted into nude mice, subcutaneous solid tumors at the transplanted sites were formed and splenomegaly and lymphadenopathy were induced. These transplantable cells wer...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.9.5691-5695.1992
更新日期:1992-09-01 00:00:00
abstract::R325-beta TK+, a herpes simplex virus 1 mutant carrying a 500-base-pair deletion in the alpha 22 gene and the wild-type (beta) thymidine kinase (TK) gene, was previously shown to grow efficiently in HEp-2 and Vero cell lines. We report that in rodent cell lines exemplified by the Rat-1 line, plating efficiency was red...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.55.2.338-346.1985
更新日期:1985-08-01 00:00:00
abstract::The entry of the viral genomic DNA of cauliflower mosaic virus into the nucleus is a critical step of viral infection. We have shown by transient expression in plant protoplasts that the viral coat protein (CP), which is processed from the product of open reading frame IV, contains an N-terminal nuclear localization s...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.1.553-560.1999
更新日期:1999-01-01 00:00:00
abstract::Antigens detected by the complement-fixation (CF) test were prepared from BHK-21 cells infected with Pichinde virus. The preparations contained two antigens demonstrable by immunodiffusion. The antigen present in abundance was heat stable, Pronase resistant, and had a molecular weight of 20,000 to 30,000 as estimated ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.22.1.175-186.1977
更新日期:1977-04-01 00:00:00
abstract::Chemokine receptors CCR5 and CXCR4 are the primary fusion coreceptors utilized for CD4-mediated entry by macrophage (M)- and T-cell line (T)-tropic human immunodeficiency virus type 1 (HIV-1) strains, respectively. Here we demonstrate that HIV-1 Tat protein, a potent viral transactivator shown to be released as a solu...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.11.8952-8960.1998
更新日期:1998-11-01 00:00:00
abstract::The presence of porcine endogenous retroviruses presents a potential risk of transmission of infectious diseases (xenozoonosis) if tissues and organs from genetically modified pigs are to be used in xenotransplantation. Here, we report that intracellular expression of a llama single-domain antibody against p15, the ma...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.22.12132-12139.2003
更新日期:2003-11-01 00:00:00
abstract::LA3382 is a temperature-sensitive replication-defective mutant of Rous sarcoma virus that contains four active mutations. In this study we performed experiments to determine the biochemical defect that blocks the synthesis of infections virus late in the replication cycle. At the nonpermissive temperature (41 degrees ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.40.3.752-761.1981
更新日期:1981-12-01 00:00:00
abstract:UNLABELLED:Giardia lamblia virus (GLV) is a small, nonenveloped, nonsegmented double-stranded RNA (dsRNA) virus infecting Giardia lamblia, the most common protozoan pathogen of the human intestine and a major agent of waterborne diarrheal disease worldwide. GLV (genus Giardiavirus) is a member of family Totiviridae, al...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02745-14
更新日期:2015-01-15 00:00:00
abstract::Intrarectal simian immunodeficiency virus (SIV) infection in rhesus macaques is a model for sexual transmission of primate retroviruses. Phylogenetic studies on envelope gene sequences that were present in blood following intrarectal SIV inoculation provided evidence for selective amplification of a subset of viruses ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.10.6876-6883.1996
更新日期:1996-10-01 00:00:00
abstract::Molluscum contagiosum virus (MCV), the only member of the Molluscipoxvirus genus, causes benign papules in healthy people but disfiguring lesions in immunocompromised patients. The sequence of MCV has been completed, revealing that MCV encodes a probable type I topoisomerase enzyme. All poxviruses sequenced to date al...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.4.3401-3406.1998
更新日期:1998-04-01 00:00:00
abstract::T7+ phage are unable to plate on a strain of Shigella sonnei D2 371-48. Spontaneous phage mutants arise (ss--mutants) that are able to plate on this strain of Shigella. We have shown by complementation studies and genetic crosses that the ss--mutation maps in gene 10, the structural gene for the major protein of the c...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.22.3.694-701.1977
更新日期:1977-06-01 00:00:00
abstract::CCCTC-binding factor (CTCF) has been implicated in various aspects of viral and host chromatin organization and transcriptional control. We showed previously that CTCF binds to a cluster of three sites in the first intron of the Kaposi's sarcoma-associated herpesvirus (KSHV) multicistronic latency-associated transcrip...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02283-12
更新日期:2013-02-01 00:00:00
abstract::The structures of DNAs present in various intracellular forms of simian virus 40 (SV40) nucleoprotein complexes were analyzed by micrococcal nuclease digestion. The results showed that the 70S SV40 chromatin was completely sensitive to nuclease digestion, whereas CsCl gradient-purified mature virion was completely res...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.44.2.603-609.1982
更新日期:1982-11-01 00:00:00
abstract::To evaluate the possibility of producing transducible replication-defective hepadnaviruses, cloned mutant duck hepatitis B virus genomes were tested both for virus antigen production and viral DNA synthesis following transfection into the human hepatoma cell line HuH7. Deletion of a cis-acting 12-nucleotide sequence i...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.2.642-650.1990
更新日期:1990-02-01 00:00:00
abstract::Retrovirus particles each contain two copies of the viral genome in the form of a noncovalently linked RNA dimer. Earlier studies have mapped a cis-acting region near the 5' end of the human immunodeficiency virus type 1 (HIV-1) genome, termed the psi locus, which appears essential for initiation of genomic dimerizati...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.5.3407-3414.1997
更新日期:1997-05-01 00:00:00
abstract::Simian varicella virus (SVV) and varicella-zoster virus (VZV) are closely related alphaherpesviruses that cause varicella (chickenpox) in nonhuman primates and humans, respectively. After resolution of the primary disease, SVV and VZV establish latent infection of neural ganglia and may later reactivate to cause a sec...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00407-07
更新日期:2007-08-01 00:00:00
abstract::Sequences present at the genomic termini of herpesviruses become linked during lytic-phase replication and provide the substrate for cleavage and packaging of unit length viral genomes. We have previously shown that homologs of the consensus herpesvirus cleavage-packaging signals, pac1 and pac2, are located at the lef...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.1.320-329.1998
更新日期:1998-01-01 00:00:00