Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00572 (Asn)
 11,732 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Five strains of influenza C virus were isolated and passaged in the amniotic sacs of embryonated hens' eggs, or in the HMV-II line of human malignant melanoma cells, and were tested for reactivity with a panel of monoclonal antibodies to the hemagglutinin-esterase (HE) glycoprotein. It was observed with two strains (C/Yamagata/4/88, C/Yamagata/7/88) that the HE of virus passaged in HMV-II cells was antigenically distinguishable from that of virus cultivated in eggs. Virus clones obtained after repeated passages of these two strains in HMV-II cells all showed a significant increase in the ability to replicate in the cell culture compared to clones derived from viruses grown in eggs. No difference was seen, by contrast, in the ability to grow in eggs between HMV-II- and egg-derived virus clones. It was also found that HMV-II-grown viruses but not egg-grown viruses could agglutinate glutaraldehyde-fixed chicken erythrocytes at 23 degrees. These observations, taken together, suggest that isolation and passage of influenza C virus in HMV-II cells sometimes result in selection of antigenically distinct variants which have an advantage in binding to the cell surface receptors. Sequence analyses of the HE genes revealed that compared to egg-grown viruses, HMV-II-adapted variant of the Yamagata/4/88 strain had a single amino acid substitution in the HE molecule at position 283 (Asp----Asn) and that of the Yamagata/7/88 strain had two substitutions at positions 212 (Glu----Lys) and 519 (Asn----Asp).
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PMID:Selection of antigenically distinct variants of influenza C viruses by the host cell. 164 87

Evidence is presented for an endogenous route of Ag processing for CD4+ T cell recognition of influenza hemagglutinin that requires obligatory traffic of de novo synthesized hemagglutinin across the lumen of the endoplasmic reticulum for processing in a cytosolic compartment. I-Ad-restricted T cell clones that recognize synthetic peptides corresponding to two distinct antigenic regions of the HA1 subunit, HA1 56-76 and HA1 177-199, are cytotoxic and, dependent on epitope specificity can recognize endogenously processed Ag and lyse class II+ target cells infected with a recombinant vaccinia-X31 HA virus. HA1 56-76 specific T cell clones fail to recognize (target cells infected with) influenza X31 viruses, containing a single residue change, HA1 63 Asp----Asn that introduces an oligosaccharide attachment site: Asp63Cys64Thr65. Recognition is restored, however, by tunicamycin treatment of mutant virus infected target cells. Inasmuch as N-glycosylation of nascent hemagglutinin polypeptides occurs in the lumen of the endoplasmic reticulum, this indicates a route of endogenous processing for hemagglutinin, requiring transport across the endoplasmic reticulum, which has been confirmed by the failure of CD4+ T cells to recognize a recombinant VACC-hemagglutinin virus in which the same single residue change, HA1 63 Asp----Asn has been introduced by site directed mutagenesis.
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PMID:The role of the endoplasmic reticulum in antigen processing. N-glycosylation of influenza hemagglutinin abrogates CD4+ cytotoxic T cell recognition of endogenously processed antigen. 169 Jul 78

Information on the antigenic structure of influenza hemagglutinin (HA) has been deduced previously from sequence analyses of laboratory mutant viruses selected, in vitro, with neutralizing monoclonal antibody (mAb) established exclusively from BALB/c (H-2d) mice; and there has been no attempt to investigate the influence of host genetic background, or natural route of infection, on the protective antibody repertoire. CBA/Ca mice are extremely sensitive to X31 virus infection, and in the present study a structural analysis was made of the antibody repertoire, by direct sequencing of the HA genes of laboratory mutant viruses selected, in ovo with mAb from CBA/Ca mice primed by natural infection with X31 virus at two different infectious doses. Single nucleotide substitutions in the HA genes of mutant viruses identified both novel and immunodominant antigenic sites on the HA1 subunit: a majority of mAbs, from different donors, were of the IgG2a isotype and were specific for HA1 158 Gly. In addition, novel laboratory mutants were obtained containing substitutions in the HA1 subunit that had not been reported previously for H3 subtype viruses, either natural variants or laboratory mutants, at residues: HA1 62 Ile----Arg; HA1 165 Asn----Ser (resulting in the loss of a N-glycosylation site); and HA1 273 Pro----Leu. Our findings suggest that host genetic background and/or a natural route of infection may be significant factors in the selection of different and distinct neutralizing antibody responses to influenza HA and therefore be of some relevance in our further understanding of the immune pressure for antigenic drift, and the immunogenic features of a protective antigen.
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PMID:Structural assignment of novel and immunodominant antigenic sites in the neutralizing antibody response of CBA/Ca mice to influenza hemagglutinin. 170 53

Analysis of canine parvovirus (CPV) isolates with a panel of monoclonal antibodies showed that after 1986, most viruses isolated from dogs in many parts of the United States differed antigenically from the viruses isolated prior to that date. The new antigenic type (designated CPV type 2b) has largely replaced the previous antigenic type (CPV type 2a) among virus isolates from the United States. This represents the second occurrence of a new antigenic type of this DNA virus since its emergence in 1978, as the original CPV type (CPV type 2) had previously been replaced between 1979 and 1981 by the CPV type 2a strain. DNA sequence comparisons showed that CPV types 2b and 2a differed by as few as two nonsynonymous (amino acid-changing) nucleotide substitutions in the VP-1 and VP-2 capsid protein genes. One mutation, resulting in an Asn-Asp difference at residue 426 in the VP-2 sequence, was shown by comparison with a neutralization-escape mutant selected with a non-CPV type 2b-reactive monoclonal antibody to determine the antigenic change. The mutation selected by that monoclonal antibody, a His-Tyr difference in VP-2 amino acid 222, was immediately adjacent to residue 426 in the three-dimensional structure of the CPV capsid. The CPV type 2b isolates are phylogenetically closely related to the CPV type 2a isolates and are probably derived from a common ancestor. Phylogenetic analysis showed a progressive evolution away from the original CPV type. This pattern of viral evolution appears most similar to that seen in some influenza A viruses.
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PMID:Rapid antigenic-type replacement and DNA sequence evolution of canine parvovirus. 194 46

During the epidemic outbreak in the region of Greifswald in the winter 1974/75, we found influenza virus variants which showed differences in the electrophoretic mobility of HA. Among the 25 isolates 13 were of slower and 12 of higher mobility. HA1 of 6 isolates was studied by determining the number of the carbohydrate side chains and by direct sequencing of vRNA. Evidence is presented that variants showing a slower electrophoretic mobility of HA1 had consistently acquired a seventh carbohydrate side chain at Asn 126 in epitope A. All the isolates differed from the reference strain A/Port Chalmers/1/73 by the loss of the oligosaccharide at Asn 81. The field strain A/Dresden/3/71 possessed only 5 oligosaccharides in HA1. These results suggest that changes in glycosylation are an important mechanism in the structural variation underlying antigenic drift of HA.
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PMID:Intraepidemic variants of influenza virus H3 hemagglutinin differing in the number of carbohydrate side chains. 195 30

We have previously characterized an influenza A (H1N1) virus which has host-dependent growth and receptor binding properties and have shown that a mutation which removes an oligosaccharide from the tip of the hemagglutinin (HA) by changing Asn-129 to Asp permits this virus to grow to high titer in MDBK cells, (C. M. Deom, A. J. Caton, and I. T. Schulze, Proc. Natl. Acad. Sci. USA 83:3771-3775, 1986). We have now isolated monoclonal antibodies specific for the mutant HA and have used escape mutants to identify alterations in HA sequence which reduce virus yields from MDBK cells without reducing those from chicken embryo fibroblasts. Two types of escape mutants which grow equally well in chicken embryo fibroblasts were obtained. Those with the parent phenotype contain Asn at residue 129 and are glycosylated at that site. Those with the mutant phenotype are unchanged at residue 129 but have a Gly to Glu substitution at residue 158, which is close to residue 129 on the HA1 subunit. Binding assays with neoglycoproteins containing N-acetylneuraminic acid in either alpha 2,3 or alpha 2,6 linkage to galactose showed that the MDBK-synthesized oligosaccharides at Asn-129 reduce binding to both of these receptors, leaving the HA's preference for alpha 2,6 linkages unchanged. Glu at residue 158 greatly reduces binding to both receptors without reducing virus yields from MDBK cells. We conclude that changes in the receptor binding properties of the HA can result either from direct alteration of the HA protein by host cell glycosylation or from mutations in the HA gene and that these changes generate heterogeneity that can contribute to the survival of influenza A virus populations in nature.
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PMID:Single amino acid substitutions in the hemagglutinin can alter the host range and receptor binding properties of H1 strains of influenza A virus. 203 64

Normal bovine and mouse sera contain a component, termed beta inhibitor, that inhibits the infectivity and hemagglutinating activity of influenza A viruses of the H1 and H3 subtypes. To investigate the nature of the interaction of beta inhibitors with influenza A viruses we isolated a mutant of the virus Mem71H-BelN (H3N1) that could grow in the presence of bovine serum. The mutant virus was resistant to hemagglutination inhibition by mouse serum as well as by bovine serum and had undergone changes in the receptor-binding and the antigenic properties of its hemagglutinin (HA) molecule. Sequence analysis of the HA genes of parent and mutant viruses revealed a single nucleotide change in the mutant, resulting in the substitution Thr----Asn at residue 167 of the HA1 chain of HA. This change leads to loss of the potential glycosylation site Asn-165-Val-166-Thr-167 at the tip of the HA spike, which in viruses of the H3 subtype is known to bear a high-mannose (type II) carbohydrate side chain N-linked to Asn-165. The association of beta inhibitor resistance with loss of this carbohydrate side chain suggested that beta inhibitors may be lectins. In support of this hypothesis, treatment of the beta inhibitor-sensitive parent virus Mem71H-BelN with periodate converted it to the resistant state. Furthermore, the inhibitory activity of both bovine and mouse sera for the parental virus was abrogated by D-mannose. We conclude that the beta inhibitors in bovine and mouse sera are mannose-binding lectins that inhibit hemagglutination and neutralize virus infectivity by binding to carbohydrate at the tip of the HA spike, blocking access of cell-surface receptors to the receptor-binding site on HA.
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PMID:Bovine and mouse serum beta inhibitors of influenza A viruses are mannose-binding lectins. 216 43

Electrophoresis in polyacrylamide gel of the reference influenza A/Victoria/35/72 (H3N2) virus and its persisting variants (PV) showed that the PV isolated on the 158th day from the moment of persistence modelling (PV158) had mutation in the gene of hemagglutinin (HA). This mutation is manifested by incomplete HA synthesis at 40 degrees C and increase of mobility of the light HA subunit (HA2). Analysis of nucleotide sequence of the greater part of HA gene of PV158 virus revealed 5 nucleotide substitutions four of which were significant. Three substitutions were found in Hal: 219 (Ser----Phe), 220 (Arg----Gly), 226 (Leu----Gln) and one in HA2: 156 (Thr----Asn). The importance of these mutations in the determination of the PV phenotype is discussed.
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PMID:[The characteristics of the hemagglutinin from persistent variants of the influenza virus A/Victoria/35/72 (H3N2)]. 226 78

A total of 14 I-Ad-restricted helper T-cell clones specific for the hemagglutinin (HA) molecule of influenza virus were isolated from spleens of BALB/c or (BALB/c X C57BL/10)F1 mice immunized with the H3 subtype influenza virus A/Memphis/71 (Mem 71) and from lymph nodes of BALB/c mice primed with purified HA. The specificity of these T-cell clones was assessed in proliferation assays by reactivity with naturally occurring strains of viruses that arose by antigenic drift and contain known amino acid sequence changes in HA and with a panel of monoclonal antibody (MAb)-selected mutants of Mem 71 with single amino acid substitutions in HA. The HA genes of those mutant viruses that failed to stimulate one or more of the T-cell clones were sequenced. The clones could be allocated to at least four groups, each group having a distinct pattern of reactivity with the panel of natural field strains. The epitopes recognized by the four groups of clones were found, by reactivity with MAb-selected mutants, to be in very close proximity to one another and probably overlapping. All of the distinct epitopes recognized by the T-cell clones were adversely affected by a single amino acid substitution, either at residue 60 or at residue 63 in the HA1 polypeptide chain, within the region known from antibody-binding studies as site E. Some, but not all, of the epitopes may be influenced by the addition of a carbohydrate side chain to the HA of a particular MAb-selected mutant and certain field strains containing an Asp----Asn substitution at residue 63. Site E is therefore a major site of H-2d helper T-cell recognition on the H3 HA.
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PMID:Distinct epitopes recognized by I-Ad-restricted T-cell clones within antigenic site E on influenza virus hemagglutinin. 244 16

We have previously demonstrated diversity in the specificity of murine, H-2k class II-restricted, T cell clones for the hemagglutinin (HA) molecule of H3N2 influenza viruses and have mapped two T cell determinants, defined by synthetic peptides, to residues 48-68 and 118-138 of HA1. In this study we examine the nature of the determinant recognized by six distinct P48-68-specific T cell clones by using a panel of truncated synthetic peptides and substituted peptide analogs. From the peptides tested, the shortest recognized were the decapeptides, P53-62 and P54-63, which suggests that the determinant was formed from the 9 amino acids within the sequence 54-62. Asn54 was critical for recognition since P49-68 (54S) was not recognized by the T cell clones. Furthermore this peptide analog was capable of competing with P48-68 for Ag presentation, thereby suggesting that residue 54 is not involved in Ia interaction and may therefore be important for TCR interaction. Residue substitutions at position 63 also affected T cell recognition, but in a more heterogeneous fashion. Peptide analogs or mutant viruses with a single amino acid substitution at position 63 (Asp to Asn or Tyr) reduced the responses of the T cell clones to variable extents, suggesting that Asp63 may form part of overlapping T cell determinants. However since the truncated peptide P53-62 was weakly recognized, then Asp63 may not form part of the TCR or Ia interaction site, but may affect recognition through a steric or charge effect when substituted by Asn or Tyr. Ag competition experiments with the two unrelated HA peptides, P48-68 and P118-138, recognized by distinct T cell clones in the context of the same restriction element (I-Ak), showed that the peptides did not compete for Ag presentation to the relevant T cell clones, whereas a structural analog of P48-68 was a potent inhibitor. This finding is discussed in relation to the nature of the binding site for peptide Ag on the class II molecule.
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PMID:Fine specificity of murine class II-restricted T cell clones for synthetic peptides of influenza virus hemagglutinin. Heterogeneity of antigen interaction with the T cell and the Ia molecule. 245 66


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