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PubMed1997

Reactivity of synthetic peptides representing selected sections of hepatitis C virus core and envelope proteins with a panel of hepatitis C virus-seropositive human plasma.

A series of 54 synthetic peptides, 15-20 residues long, that represented selected parts of the structural proteins of hepatitis C virus (HCV) were tested for immunoreactivity with a panel of 45 plasma samples from potential blood donors who were known to be seropositive for anti-HCV. Most of the ten peptides that represented the core protein showed reactivity with most of the panel samples. All except one of the 20 peptides that represented non-hypervariable regions of envelope proteins E1 and E2 showed little or no reactivity. In contrast, 18 of the the 24 peptides that represented variants of the hypervariable region 1 of the E2 protein reacted with at least one panel sample. Notably, 40% of the panel samples cross-reacted with two or more different peptides sequences some of which differed by more than 50%. Two panel samples each cross-reacted with seven different peptide sequences. The results suggest a broad anti-hypervariable region antibody specificity in many anti-HCV-seropositive samples and possible limits on the mutability of hypervariable region sequences. The work contributes to understanding the immunogenicity and persistence of HCV.

Amino Acid Sequence↗

PubMed2001

Form species Nostoc commune (Cyanobacteria).

The form species concept for the Cyanobacteria was evaluated using a comprehensive set of Nostoc samples that were collected during the past two centuries, from all continents, including regions from the Tropics to the Poles. Phylogenies were constructed based upon the conserved regions of tRNALeu (UAA) group I intron DNA sequences. Thirty-four forms contained a tRNALeu (UAA) intron of 284 nt. These 284-nt introns contained 200 nt of conserved sequence that, in most cases, shared 100% sequence identity, they had three variable regions (I, II and III) amounting to 84 nt, contained no hypervariable region and formed a discrete cluster in phylogenetic analysis. These forms represented 31 independent populations in both hemispheres and constitute examples of form species Nostoc commune. Multiple introns were obtained from several of the populations. Ten populations contained introns of 287-340 nt with a hypervariable region, 8 to 59 nt in length, located between variable regions I and II. Alignments identified 15 examples where 5'-AAAAUCC-3' occurred at the hypervariable region-variable region II boundary; this sequence is identical to the conserved sequence at the 3' intron-exon boundary (splice site) within the tRNALeu (UAA) gene. The possibility that hypervariable regions were removed from the primary intron through secondary splicing was tested in vitro but proved to be negative under the experimental conditions used. Shared morphologies of genetically different strains, dissimilar morphologies in strains that share identical genetic markers, incorrect naming of culture collection strains and genetic drift in cultured strains emphasize that the successful delineation of cyanobacterial species requires the application of multiple taxonomic criteria.

Base Sequence↗

PubMed1992

Structural repertoire of the human VH segments.

The VH gene segments produce the part of the VH domains of antibodies that contains the first two hypervariable regions. The sequences of 83 human VH segments with open reading frames, from several individuals, are currently known. It has been shown that these sequences are likely to form a high proportion of the total human repertoire and that an individual's gene repertoire produces about 50 VH segments with different protein sequences. In this paper we present a structural analysis of the amino acid sequences produced by the 83 segments. Particular residue patterns in the sequences of V domains imply particular main-chain conformations, canonical structures, for the hypervariable regions. We show that, in almost all cases, the residue patterns in the VH segments imply that the first hypervariable regions have one of three different canonical structures and that the second hypervariable regions have one of five different canonical structures. The different observed combinations of the canonical structures in the first and second regions means that almost all sequences have one of seven main-chain folds. We describe, in outline, structures of the antigen binding site loops produced by nearly all the VH segments. The exact specificity of the loops is produced by (1) sequence differences in their surface residues, particularly at sites near the centre of the combining site, and (2) sequence differences in the hypervariable and framework regions that modulate the relative positions of the loops.

Amino Acid Sequence↗

PubMed1981

Immunoglobulin heavy chains from anti-inulin myeloma proteins: evidence for a new heavy chain joining segment.

Immunoglobulin heavy chains have been shown to be encoded by at least 3 widely separated genetic elements, designated variable (V), diversity (D), and joining (J), which undergo rearrangement during somatic differentiation to produce the active gene form. The D segment codes for a portion of the 3rd hypervariable region and thus potentially contributes significantly to structural diversity in this portion of the molecule. Heavy chains from anti-inulin proteins are unusual in that they essentially lack a 3rd hypervariable region. Thus, if a D segment exists in these proteins, it is extremely short, possibly 1 to 2 amino acids, and more likely serves a framework function rather than introduces structural diversity in the 3rd hypervariable region. We have completed the heavy chain variable region amino acid sequence from proteins AMPC1 and T957 bringing to 6 the number of complete sequences from this group. All of these proteins lack a 3rd hypervariable region. In addition, substitutions are found within the J segments of AMPC1 and T957, which are unlikely to be generated by the recombination event. The occurrence of Pro at position 105 in both of these J segments in contrast to the Gln found in all other heavy chains using this J segment suggests the possible existence of a previously unidentified J segment gene.

Amino Acid Sequence↗

PubMed2005

Role of the hypervariable hinge region of phosphoprotein P of vesicular stomatitis virus in viral RNA synthesis and assembly of infectious virus particles.

The phosphoprotein (P protein) of vesicular stomatitis virus (VSV) is an essential subunit of the viral RNA-dependent RNA polymerase and has multiple functions residing in its different domains. In the present study, we examined the role of the hypervariable hinge region of P protein in viral RNA synthesis and recovery of infectious VSV by using transposon-mediated insertion mutagenesis and deletion mutagenesis. We observed that insertions of 19-amino-acid linker sequences at various positions within this region affected replication and transcription functions of the P protein to various degrees. Interestingly, one insertion mutant was completely defective in both transcription and replication. Using a series of deletion mutants spanning the hinge region of the protein, we observed that amino acid residues 201 through 220 are required for the activity of P protein in both replication and transcription. Neither insertion nor deletion had any effect on the interaction of P protein with N or L proteins. Infectious VSVs with a deletion in the hinge region possessed retarded growth characteristics and exhibited small-plaque morphology. Interestingly, VSV containing one P protein deletion mutant (PDelta7, with amino acids 141 through 200 deleted), which possessed significant levels of replication and transcription activity, could be amplified only by passage in cells expressing the wild-type P protein. We conclude that the hypervariable hinge region of the P protein plays an important role in viral RNA synthesis. Furthermore, our results provide a previously unidentified function for the P protein: it plays a critical role in the assembly of infectious VSV.

Animals↗

PubMed2005

Structural basis for segmental gene conversion in generation of Anaplasma marginale outer membrane protein variants.

Bacterial pathogens in the genus Anaplasma generate surface coat variants by gene conversion of chromosomal pseudogenes into single-expression sites. These pseudogenes encode unique surface-exposed hypervariable regions flanked by conserved domains, which are identical to the expression site flanking domains. In addition, Anaplasma marginale generates variants by recombination of oligonucleotide segments derived from the pseudogenes into the existing expression site copy, resulting in a combinatorial increase in variant diversity. Using the A. marginale genome sequence to track the origin of sequences recombined into the msp2 expression site, we demonstrated that the complexity of the expressed msp2 increases during infection, reflecting a shift from recombination of the complete hypervariable region of a given pseudogene to complex mosaics with segments derived from hypervariable regions of different pseudogenes. Examination of the complete set of 1183 variants with segmental changes revealed that 99% could be explained by one of the recombination sites occurring in the conserved flanking domains and the other within the hypervariable region. Consequently, we propose an 'anchoring' model for segmental gene conversion whereby the conserved flanking sequences tightly align and anchor the expression site sequence to the pseudogene. Associated with the recombination sites were deletions, insertions and substitutions; however, these are a relatively minor contribution to variant generation as these occurred in less than 2% of the variants. Importantly, the anchoring model, which can account for more variants than a strict segmental sequence identity mechanism, is consistent with the number of msp2 variants predicted and empirically identified during persistent infection.

Amino Acid Sequence↗

PubMed1991

Importance of purine and pyrimidine content of local nucleotide sequences (six bases long) for evolution of the human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 evolves rapidly, and random base change is thought to act as a major factor in this evolution. However, segments of the viral genome differ in their variability: there is the highly variable env gene, particularly hypervariable regions located within env, and, in contrast, the conservative gag and pol genes. Computer analysis of the nucleotide sequences of human immunodeficiency virus type 1 isolates reveals that base substitution in this virus is nonrandom and affected by local nucleotide sequences. Certain local sequences 6 base pairs long are excessively frequent in the hypervariable regions. These sequences exhibit base-substitution hotspots at specific positions in their 6 bases. The hotspots tend to be nonsilent letters of codons in the hypervariable regions--thus leading to marked amino acid substitutions there. Conversely, in the conservative gag and pol genes the hotspots tend to be silent letters because of a difference in codon frame from the hypervariable regions. Furthermore, base substitutions in the local sequences that frequently appear in the conservative genes occurred at a low level, even within the variable env. Thus, despite the high variability of this virus, the conservative genes and their products could be conserved. These may be some of the strategies evolved in human immunodeficiency virus type 1 to allow for positive-selection pressures, such as the host immune system, and negative-selection pressures on the conservative gene products.

Acquired Immunodeficiency Syndrome↗

PubMed1975

Structural studies on induced antibodies with defined idiotypic specificities. I. The heavy chains of anti-p-azophenylarsonate antibodies from A/J mice bearing a cross-reactive idiotype.

Amino acid sequence analysis has been performed on three groups of heavy (H) chains of A/J mice. H chains derived from unimmunized animals were compared to anti-p-azophenylarsonate (anti-Ar) antibodies which were further subdivided into those possessing and those depleted of a cross-reacting idiotype (CRI). It was found that anti-Ar antibodies bearing the CRI are homogeneous through the first hypervariable region of the H chain. The same sequence was obtained for pooled antibody isolated from the ascites fluid of 18 A/J mice or from a single mouse. The H chains appear to belong to a minor V-H subgroup. In the first 30 positions Anti-Ar antibodies depleted of the CRI had the same sequence as those containing the CRI (with small amounts of heterogeneity at some positions), but contained a mixture of sequences in the first hypervariable region of the H chain. These studies indicate that antibodies with similar specificity and with identical framework sequences, but which differ in their hypervariable regions, contain different idiotypic determinants, and support the concept that the idiotypic determinants reside primarily within hypervariable regions.

Amino Acid Sequence↗

PubMed1987

Allelic variation in the DR subregion of the human major histocompatibility complex.

Allelic variation in the DR subregion of the human major histocompatibility complex has been analyzed by nucleic acid sequencing of cDNA clones obtained from cell lines homozygous by consanguinity for all the common serological types DR1-9. Two expressed loci were identified in the haplotypes DR2, -3, -4, -7, and -9; one locus being present at a much lower frequency (4-7%) than the other. The low-frequency allele was highly conserved between each of the DRw53 (DR4, -7, -9) and the DRw52 (DR3, -5, -6) haplotypes. Analysis of the variation between alleles confirms the presence of three allelic hypervariable regions. At each variable residue, a limited range of amino acid substitutions are found, distinguishing them from immunoglobulin hypervariable regions. Dinucleotide substitutions are extremely common. Individual hypervariable regions are often shared between haplotypes. Much of the variation in these alleles can be attributed to the shuffling of these regions between haplotypes, possibly by the mechanism of gene conversion.

Alleles↗

PubMed1999

Sequence variation within the capsid protein of Australian isolates of feline calicivirus.

The capsid protein of Australian feline calicivirus (FCV) isolates is demonstrably different from the prototype strain F9. Five Australian isolates of FCV, dating from 1970 to 1989, were analysed by western blotting and immunoprecipitation. Varying reactivity to a panel of F9 specific monoclonal antibodies (MAbs) was observed. DNA sequencing of RT-PCR generated clones supported the observation of variation between capsid proteins. Predicted amino acid sequences varied by 11 to 17.5% across the whole capsid when compared to the published F9 sequence. Differences in amino acid sequence were most apparent in previously described hypervariable regions (C and E). Within hypervariable region E differences of 22 to 34% were observed compared to F9. The observed lack of reactivity to F9 MAbs correlated with amino acid changes within previously characterized binding sites within region E.

Amino Acid Sequence↗

PubMed2006

Two monoclonal antibodies with defined epitopes of P44 major surface proteins neutralize Anaplasma phagocytophilum by distinct mechanisms.

Anaplasma phagocytophilum is an obligatory intracellular bacterium that causes human granulocytic anaplasmosis. The polymorphic 44-kDa major outer membrane proteins of A. phagocytophilum are dominant antigens recognized by patients and infected animals. However, the ability of anti-P44 antibody to neutralize the infection has been unclear due to a mixture of P44 proteins with diverse hypervariable region amino acid sequences expressed by a given bacterial population and lack of epitope-defined antibodies. Monoclonal antibodies (MAbs) 5C11 and 3E65 are directed to different domains of P44 proteins, the N-terminal conserved region and P44-18 central hypervariable region, respectively. Passive immunization with either MAb 5C11 or 3E65 partially protects mice from infection with A. phagocytophilum. In the present study, we demonstrated that the two monoclonal antibodies recognize bacterial surface-exposed epitopes of naturally folded P44 proteins and mapped these epitopes to specific peptide sequences. The two MAbs almost completely blocked the infection of the A. phagocytophilum population that predominantly expressed P44-18 in HL-60 cells by distinct mechanisms: MAb 5C11 blocked the binding, but MAb 3E65 did not block binding or internalization. Instead, MAb 3E65 inhibited internalized A. phagocytophilum to develop into microcolonies called morulae. Some plasma from experimentally infected horses and mice reacted with these two epitopes. Taken together, these data indicate the presence of at least two distinct bacterial surface-exposed neutralization epitopes in P44 proteins. The results indicate that antibodies directed to certain epitopes of P44 proteins have a critical role in inhibiting A. phagocytophilum infection of host cells.

Anaplasma phagocytophilum↗

PubMed1992

The susceptibility sequence to rheumatoid arthritis is a cross-reactive B cell epitope shared by the Escherichia coli heat shock protein dnaJ and the histocompatibility leukocyte antigen DRB10401 molecule.

Immunological responses to bacterial heat shock proteins have been implicated in the pathogenesis of arthritis in animals and humans. The predicted amino acid sequence of dnaJ, a heat shock protein from Escherichia coli, contains an 11-amino acid segment that is homologous to the third hypervariable region of the human histocompatibility antigen (HLA) DRB10401 (formerly known as HLA Dw4), the part of the molecule that carries susceptibility to rheumatoid arthritis. To test the biological significance of this finding, we expressed and purified recombinant dnaJ (rdnaJ), and determined its immunologic cross-reactivity with HLA DRB10401. A rabbit antipeptide antiserum raised against the sequence of the third hypervariable region of HLA DRB10401 specifically bound to 'dnaJ, thus confirming that a similar sequence is expressed on the bacterial protein. Of greater consequence, an antiserum to the 'dnaJ protein recognized not only a peptide from the third hypervariable region of HLA DRB10401, but also the intact HLA DRB10401 polypeptide. Furthermore, the antibody to 'dnaJ reacted with HLA DRB10401 homozygous B lymphoblasts, but not with HLA DRB11501, DRB10101, DRB10301, and DRB10701 (formerly known as HLA Dw2, DR 1, DR 3, and DR 7, in the same order) homozygous cells. These results demonstrate that exposure to a bacterial heat shock protein can elicit antibodies against the rheumatoid arthritis susceptibility sequence in the third hypervariable region of HLA DRB10401.

Amino Acid Sequence↗

PubMed1998

Small subunit ribosomal RNA genes of tabanids and hippoboscids (Diptera: Brachycera): evolutionary relationships and comparison with other Diptera.

The small subunit ribosomal RNA (SSU rRNA) genes of hippoboscid (Ornithoica vicina Walker) and tabanid (Chrysops niger Macquart) Diptera were sequenced to determine their phylogenetic position within the order and to determine whether or not extensive hypervariable regions in this gene are widespread in the Diptera. A parsimony analysis of an alignment containing 8 dipteran sequences produced a single most parsimonious tree that placed O. vicina as sister group to Drosophila melanogaster Meigen. The tabanid Chrysops niger was sister group to the asilomorphan taxa, and the sister group to the Brachycera was a Tipula sp. although this relationship was not supported by bootstrap analysis. The hippoboscid and tabanid sequences contain extensive hypervariable regions in the V2, V4, V6, and V7 regions as do other Diptera. When these regions of the alignment were excluded from the phylogenetic analysis, a single most parsimonious tree was found. This tree had an identical overall topology to the tree obtained from the total data set. The hypervariable regions in parts of the dipteran SSU rRNA genes were more extensive in the nematocerous dipteran sequences used in this study than in the other dipteran representatives; these hypervariable regions may be of more utility in inferring relationship among species and subspecies than at the suprageneric level.

Animals↗

PubMed2002

Genetic variability and stability of Anaplasma phagocytophila msp2 (p44).

Anaplasma (Ehrlichia) phagocytophila's major immunodominant surface protein antigen, Msp2 (P44, 44-kDa antigen), is encoded by a family of paralogous genes characterized by conserved sequences flanking a hypervariable region. The antigenic profiles of most strains of A. phagocytophila are different, and the differences are principally related to Msp2 expression. To date, multiple unique msp2 gene paralogs have been found in A. phagocytophila isolates, but the overall number in the genome of a single strain is not yet known. Changes in msp2 expression may be related to antigenic variability; thus, we examined the minimal complement of msp2 genes or pseudogenes in two strains of A. phagocytophila and the number of transcriptionally active msp2 gene paralogs during low-passage, steady-state, in vitro propagation. Of 15 BDS strain clones, 1 had a hypervariable region identical to the region in a clone obtained from a BDS strain genomic library previously prepared from organisms after only two horse passages. When 124 Webster strain clones were examined, 18 unique hypervariable regions were identified. Of 64 Webster strain cDNA clones, 56 (87.5%) were derived from a single gene, and transcripts from six additional msp2 genes were also identified. The sequences of several hypervariable regions that were > or = 97% similar to regions present in other strains were identified by performing a BLAST analysis of sequences deposited in the GenBank database. These findings suggest that antigenic variability results from transcription of one or a few of the multiple paralogs and not from genetic instability that results in random accumulated mutations, although the possibility that gene recombination plays a role cannot be eliminated. The predominant Msp2 pattern in vitro is determined by transcription from a single gene.

Anaplasma↗

PubMed1993

Hypervariable-control-region sequences reveal global population structuring in a long-distance migrant shorebird, the Dunlin (Calidris alpina).

Hypervariable segments of the control region of mtDNA as well as part of the cytochrome b gene of Dunlins were amplified with PCR and sequenced directly. The 910 base pairs (bp) obtained for each of 73 individuals complete another of the few sequencing studies that examine the global range of a vertebrate species. A total of 35 types of mtDNA were detected, 33 of which were defined by the hypervariable-control-region segments. Thirty of the latter were specific to populations of different geographic origin in the circumpolar breeding range of the species. The remaining three types indicate dispersal between populations in southern Norway and Siberia, but female-mediated flow of mtDNA apparently is too low to overcome the effects of high mutation rates of the control-region sequences, as well as population subdivision associated with historical range disjunctions. A genealogical tree relating the types grouped them into five populations: Alaska, West Coast of North America, Gulf of Mexico, western Europe, and the Taymyr Peninsula. The Dunlin is thus highly structured geographically, with measures of mutational divergence approaching 1.0 for fixation of alternative types in different populations. High diversity of types within populations as well as moderate long-term effective population sizes argue against severe population bottlenecks in promoting this differentiation. Instead, population fragmentation in Pleistocene refuges is the most plausible mechanism of mtDNA differentiation but at a much earlier time scale than suggested previously with morphometric data.

Animals↗

PubMedDate not supplied

Molecular characterization of seven field isolates of infectious bursal disease virus obtained from commercial broiler chickens.

Specific-pathogen-free sentinel birds were used as an initial biological system to isolate infectious bursal disease virus (IBDV) field isolates from commercial broiler farms exhibiting recurrent respiratory problems and poor performance. Reverse transcription (RT)-polymerase chain reaction (PCR) was used to amplify a 248-bp product encompassing the hypervariable region of the IBDV VP2 gene. Restriction fragment length polymorphism (RFLP) analysis of the RT-PCR products was performed with the restriction endonucleases DraI, SadI, TaqI, StyI, BstNI, and SspI. Two isolates (619 and 850) exhibited a RFLP pattern characteristic of Delaware variant E IBDV. Restriction enzyme digestion for four isolates (625, 849, 853, and 11,153) revealed unmatched RFLP patterns when compared with reference IBDV strains. Nucleotide and deduced amino acid sequence analyses of the VP2 hypervariable region for these six isolates revealed identity (96.3% up to 98%) with Delaware E variant IBDV strain. However, serine at position 254, which is characteristic of Delaware variant strains, was substituted by asparagine in these six isolates. The seventh IBDV isolate (9109) also exhibited a unique RFLP pattern, which included the SspI restriction site, which is characteristic of very virulent (vv) IBDV strains. Nucleotide and amino acid sequence analyses of the hypervariable region for this isolate revealed identity (90%) with the standard challenge strain. However, the leucine residue at position 294 was substituted by isoleucine. This substitution corresponds to one of the amino acids that are conserved in the vvIBDV strains. Antigenic index studies of the predicted amino acid sequence of the hypervariable region of VP2 from isolates 619, 625, 849, 850, 853, and 11,153 exhibited a profile almost identical to variant E, whereas the isolate 9109 exhibited a profile characteristic of standard IBDV strains.

Amino Acid Sequence↗

PubMed2000

High-affinity interaction between gram-negative flagellin and a cell surface polypeptide results in human monocyte activation.

Flagella from diverse gram-negative bacteria induce tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) synthesis by human monocytes (F. Ciacci-Woolwine, P. F. McDermott, and S. B. Mizel, Infect. Immun. 67:5176-5185, 1999). In this study, we establish that purified flagellin (FliC or FljB), the major filament protein from Salmonella enterica serovar Enteritidis, S. enterica serovar Typhimurium, and Pseudomonas aeruginosa, is an extremely potent inducer of TNF-alpha production by human monocytes and THP-1 myelomonocytic cells. Fifty percent of maximal TNF-alpha production (EC(50)) was obtained with 1.5 x 10(-11) M flagellin (0.75 ng/ml). Mutagenesis studies revealed that the central hypervariable region of flagellin is essential for the TNF-alpha-inducing activity of the protein. Although less active than the wild-type protein, a Salmonella flagellin mutant composed of only the central hypervariable region retained substantial TNF-alpha-inducing activity at nanomolar concentrations. In contrast, the conserved amino- and carboxy-terminal regions are inactive. Mutational analysis of the hypervariable region revealed that it contains two equally active TNF-alpha-inducing domains. The ability of THP-1 cells to respond to purified flagellins is dramatically reduced by mild trypsin treatment of the cells. Taken together, our results demonstrate that the cytokine-inducing activity of flagellins from gram-negative bacteria results from the interaction of these proteins with high-affinity cell surface polypeptide receptors on monocytes.

Cells, Cultured↗

PubMed1991

DNA typing for class II HLA antigens with allele-specific or group-specific amplification. V. Typing for subsets of HLA-DR1 and DR'Br'.

Three DRB1 alleles of the DR1 group including DRB1*0101, DRB1*0102, and DRB1*0103 are currently recognized. The first two of these are defined as HLA-DR1 by serologic typing and as either Dw1 or Dw20 by typing with T cells. DRB1*0103, previously called DR'Br' or DR'BON', is not detectable by serology. Little information exists about the population frequencies of DRB1*0102 and DRB1*0103. In the present study we have used the polymerase chain reaction (PCR) and allele-specific oligonucleotide probes to determine these alleles. To avoid cross-hybridization with other DRB genes having the same DNA sequences as those of the region to be analyzed, we performed group-specific PCR to amplify only DR1 DRB1 genes. This was accomplished using a 21-nucleotide-long primer, homologous to the first hypervariable region common to the DR1 DRB1 genes, and which under appropriate conditions amplified only DRB1 genes of the DR1 group. Five oligonucleotide probes, one matching the second hypervariable region, two spanning the third hypervariable region, and two covering codons 82 through 89, were used to determine the three alleles. DRB1*0101 (Dw1) was found to be the major type of DR1 in North American Caucasians. In North American black and Brazilian mestizo populations DRB1*0102 (Dw20) was more prevalent. DRB1*0103 (DR'Br') was detected in only six individuals in the present study.

Alleles↗