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1.
Eva Mertens Shessy Torres Marie-Pascale Frenkiel Alexander A. Khromykh 《Virology》2010,399(1):176-185
The interferon-inducible 2′,5′-oligoadenylate synthetase 1b (Oas1b) protein inhibits West Nile virus (WNV) infection by preventing viral RNA (vRNA) accumulation in infected cells. Serial passage of WNV in Oas1b-expressing mouse cells selected a virus variant with improved growth capacity. Two major amino acid substitutions were identified in this Oas1b-resistant WNV variant: NS3-S365G in the ATPase/helicase domain of NS3 and 2K-V9M in the C-terminal segment of NS4A. To assess their effect on antiviral activity of Oas1b, the NS3 and 2K mutations were engineered into an infectious WNV cDNA clone. The NS3 mutation alters requirement of ATP for ATPase activity and attenuates Oas1b-mediated suppression of vRNA accumulation. However, growth of NS3-mutant virus remains impaired in Oas1b-expressing cells. Only the 2K-V9M mutation efficiently rescued viral growth by promoting vRNA replication. Thus, WNV resistance to Oas1b antiviral action could be attributed to the 2K-V9M substitution with a potential role of NS3-S365G through rescue of vRNA accumulation. 相似文献
2.
Sushma A. Ogram 《Virology》2010,397(1):14-22
In this study, we showed that the 5′CL-PCBP complex, 3′ poly(A) tail and viral protein 2Apro are all required for optimal translation of PV RNA. The 2Apro-mediated stimulation of translation was observed in the presence or absence of both the 5′CL and the 3′ poly(A) tail. Using protein-RNA tethering, we established that the 5′CL-PCBP complex is required for optimal viral RNA translation and identified the KH3 domain of PCBP2 as the functional region. We also showed that the 5′CL-PCBP complex and the 3′ poly(A) tail stimulate translation independent of each other. In addition to the independent function of each element, the 5′CL and the 3′ poly(A) tail function synergistically to stimulate and prolong translation. These results are consistent with a model in which the 5′CL-PCBP complex interacts with the 3′ poly(A)-PABP complex to form a 5′-3′ circular complex that facilitates ribosome reloading and stimulates PV RNA translation. 相似文献
3.
Synergistic antiviral activity of Sofosbuvir and type‐I interferons (α and β) against Zika virus
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Beth Snyder Scott Goebel Fusataka Koide Roger Ptak Raj Kalkeri 《Journal of medical virology》2018,90(1):8-12
Zika virus (ZIKV) is transmitted by mosquitoes and causes Dengue‐like illness, neurological symptoms such as Guillain‐Barré Syndrome and microcephaly in children born to infected pregnant mothers. Recently, the World Health Organization (WHO) declared ZIKV infection as a Global Health Emergency. However, there are no known prophylactic or therapeutic measures against this virus. As a proof of concept toward combination therapeutic strategy against ZIKV, combinations of host‐targeted (Interferon‐α and Interferon‐β) and direct acting (Sofosbuvir) antivirals were evaluated in a hepatic cell line (Huh7) using a Cytoprotection (CP) assay. The combination of these antivirals resulted in synergistic inhibition of ZIKV infection in the in vitro CP assay. Additional testing in a ZIKV yield assay demonstrated that combination treatment of these antivirals conferred >2‐log reduction in the release of viral RNA. Measurement of ZIKV proteins in the cells infected with multiple ZIKV strains isolated from different geographical regions (Americas, Asia, and Africa) using an immunofluorescence assay confirmed the effective antiviral activity of this combination against ZIKV. These results demonstrate the in vitro proof of concept (POC) for using a combination approach utilizing the strengths of both virus and host‐targeted antivirals. These results suggest the effectiveness of the combination strategy in combating ZIKV, in the in vitro systems. Further evaluation of such combination therapies in vivo might provide an impetus for the development of effective ZIKV therapeutic strategies. 相似文献
4.
Siriruk Sarawaneeyaruk 《Virology》2009,391(1):107-178
The genome of Red clover necrotic mosaic virus (RCNMV) consists of RNA1 and RNA2, both lacking a cap structure and a poly(A)tail. RNA1 has a translational enhancer element (3′TE-DR1) in the 3′ untranslated region (UTR). In this study, we analyzed the roles of 5′ and 3′ UTRs of RNA1 in 3′TE-DR1-mediated cap-independent translation in cowpea and tobacco BY-2 protoplasts using a dual-luciferase (Luc) reporter assay system. Most mutations introduced into RNA1 5′ UTR in reporter Luc mRNA abolished or greatly reduced cap-independent translation in BY-2 protoplasts, whereas those mutations had no or much milder effects if any on translational activity in cowpea protoplasts. Our results suggest that a stem-loop structure predicted in the 5′ proximal region of RNA1 plays important roles in both translation and RNA stability. We also show that 3′TE-DR1-mediated cap-independent translation relies on a ribosome-scanning mechanism in both protoplasts. 相似文献
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6.
H. HALLBERG 《Acta physiologica (Oxford, England)》1987,129(3):421-428
The effect of β-adrenoceptor antagonists, varying in lipophilicity and receptor selectivity, were studied on tremor elicited by l -5-hydroxytryptophan (L-5-HTP) in rats pretreated with a peripherally acting decarboxylase inhibitor and a monoamine oxidase inhibitor, or by the directly acting 5-HT agonist s-methoxy-N,N-dimethyltryptamine (5-MeODMT). Plasma levels of the β-adrenoceptor antagonists were determined simultaneously. The non-selective lipophilic adrenoceptor antagonist propranolol was found to dose-dependently reduce tremor intensity, whereas the non-selective hydrophilic adrenoceptor antagonist sotalol had no effect, indicating a central site of action. Furthermore, β1-selective blockade with the adrenoceptor antagonist metoprolol had no effect on tremor intensity, whereas the β2-selective antagonist ICI 118,551 dose-dependently suppressed tremor intensity, suggesting that the β-adrenoceptor subtype involved is of the β2-type. These results suggest that blockade of centrally located β2-adrenoceptors are able to attenuate the tremor response following 5-hydroxytryptamine receptor activation. 相似文献
7.
目的 明确广东鹅流感病毒296H5 N1 亚型毒株RNA13 和RNA5 节段核苷酸全序列及其所编码蛋白的氨基酸序列,以及这些基因节段与香港禽流感病毒15697H5 N1 亚型毒株相应节段间的关系。方法 病毒粒RNA经逆转录合成cDNA,经聚合酶链反应(PCR) 扩增,产物纯化,采用双脱氧链末端终止法进行核苷酸序列测定。结果 广东鹅流感病毒296H5 N1 亚型毒株RNA13 和RNA5 节段长度分别为2341,2 341 ,2 233 和1565 个核苷酸。它们分别编码PB2( 含759 个氨基酸),PB1( 含757个氨基酸) ,PA( 含716 个氨基酸) 和NP蛋白( 含498 个核苷酸) 。这些蛋白与香港禽流感病毒15697H5 N1 亚型毒株相应蛋白氨基酸序列的同源性分别为96-4% ,97-2% ,97-3 % 和97-0% 。结论 本毒株RNA13 和RNA5 节段长度分别为2 341,2 341,2 233 和1 565 个核苷酸,它们与香港15697H5 N1 亚型毒株间存在着差异 相似文献
8.
Richard P. Ebstein Ronnen Segman Jonathan Benjamin Yamima Osher Lubov Nemanov Robert H. Belmaker 《American journal of medical genetics. Part A》1997,74(1):65-72
We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort. Am. J. Med. Genet. 74:65–72, 1997. © 1997 Wiley-Liss, Inc. 相似文献
9.
R. De Leo G. Deidda A. Novelletto S. El-Kalla A. R. Mathews L. Felicetti 《Human mutation》1995,5(4):327-328
β-thalassemia mutations were characterized in a sample of 70 patients from United Arab Emirates (U.A.E.), resulting in an enlargement of the spectrum of types found in the country. The complete association between the most common IVS I nt 5 (G-C) mutation and a specific haplotype reveals an independent origin of this mutation in U.A.E. © 1995 Wiley-Liss, Inc. 相似文献
10.
Lars
. Pedersen Anette Stryhn Thor L. Holtet Mikael Etzerodt Jens Gerwien Mogens H. Nissen Hans C. Thgersen Seren Buus 《European journal of immunology》1995,25(6):1609-1616
The function of major histocompatibility complex (MHC) class I molecules is to sample peptides derived from intracellular proteins and to present these peptides to CD8+ cytotoxic T lymphocytes. In this paper, biochemical assays addressing MHC class I binding of both peptide and β2-microglobulin (β2m) have been used to examine the assembly of the trimolecular MHC class I/β2m/peptide complex. Recombinant human β2m and mouse β2m2 have been generated to compare the binding of the two β2m to mouse class I. It is frequently assumed that human β2m binds to mouse class I heavy chain with a much higher affinity than mouse β2m itself. We find that human β2m only binds to mouse class I heavy chain with slightly (about 3-fold) higher affinity than mouse β2m. In addition, we compared the effect of the two β2m upon peptide binding to mouse class I. The ability of human β2m to support peptide binding correlated well with its ability to saturate mouse class I heavy chains. Surprisingly, mouse β2m only facilitated peptide binding when mouse β2m was used in excess (about 20-fold) of what was needed to saturate the class I heavy chains. The inefficiency of mouse β2m to support peptide binding could not be attributed to a reduced affinity of mouse β2m/MHC class I complexes for peptides or to a reduction in the fraction of mouse β2m/MHC class I molecules participating in peptide binding. We have previously shown that only a minor fraction of class I molecules are involved in peptide binding, whereas most of class I molecules are involved in β2m binding. We propose that mouse β2m interacts with the minor peptide binding (i.e. the “empty”) fraction with a lower affinity than human β2m does, whereas mouse and human β2m interact with the major peptide-occupied fraction with almost similar affinities. This would explain why mouse β2m is less efficient than human β2m in generating the peptide binding moiety, and identifies the empty MHC class I heavy chain as the molecule that binds human β2m preferentially. 相似文献