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At least 901 records · Page 50Linked to original sources
PubMed1999

Presence of multiple genotype-specific antibodies in patients with persistent infection with hepatitis C virus (HCV) of a single genotype: evidence for transient or occult superinfection with HCV of different genotypes.

OBJECTIVE: We investigated the significance of multiple genotype-specific antibodies in patients with persistent infection with hepatitis C virus (HCV) of a single genotype. METHODS: Titers of genotype-specific antibodies to group 1 and 2 HCV polypeptides in the NS4 region of HCV were measured in 53 hemophiliacs and 58 nonhemophiliacs who were persistently infected with HCV of a single genotype. In addition, sequence variability in hypervariable region 1 (HVR1) of HCV was evaluated in these patients. RESULTS: The presence of antibodies to both group 1 and 2 polypeptides, reflecting a mixture of serotypes, was more frequent in hemophiliacs (11 of 53 patients, 20.8%) than in nonhemophiliacs (two of 58 patients, 3.4%; p = 0.01). HVR1 sequence variability in 13 patients with mixed serotypes was higher than in 87 patients with a single serotype (21.1 +/- 4.3% vs 8.5 +/- 6.3%; p < 0.01). CONCLUSIONS: A mixture of HCV serotypes was more common in hemophiliacs with persistent HCV infection of a single genotype who were at high risk of exposure to HCV than in nonhemophiliacs, and the sequence variability of the infecting strains was high in these patients. These data are suggestive of the effects of superinfection with HCV of different genotypes. The presence of multiple genotype-specific antibodies to HCV may be evidence of transient or occult superinfection with HCV of different genotypes in patients with persistent infection by HCV of a single genotype.

Adolescent↗
PubMed1996

Identifying DNA polymorphisms in human TCRA/D variable genes by direct sequencing of PCR products.

The T-cell receptor (TCR) is a highly variable molecule composed of two polypeptide chains that recognize antigenic peptides in the context of major histocompatibility complex (MHC) molecules. In this study, we describe a sequence-based search for germline polymorphisms in the variable (V) gene segments of the human TCRA/D locus. Thirty different V gene segments were amplified from six to eight unrelated individuals and sequenced from low melting point agarose. Twenty-seven polymorphisms were identified in 15 V gene segments. These polymorphisms are mainly single nucleotide substitutions, but an insertion/deletion polymorphism and a single dinucleotide repeat with variable length were also seen. Of the 15 sequence variations found in the coding regions, six are silent and nine encode amino acid changes. All of the amino acid changes are found at non-conserved residues, frequently in the hypervariable regions, where they may influence MHC and/or peptide recognition. Therefore, it is possible that germline variations in TCR genes could influence an individual's immune response, and may also contribute to susceptibility to diseases such as autoimmunity.

Amino Acid Sequence↗
PubMed1996

Characterization of a new genotype II hepatitis delta virus from Taiwan.

Three genotypes of HDV, which may be associated with different clinical pictures and epidemiological patterns, have been identified. In contrast to Type I and Type III HDV, both of which have multiple isolates, Type II HDV so far includes only a single isolate (Japan-1) from a low prevalence area (Japan). Recently, Type II has been reported to be the predominant genotype in Taiwan, which is also a low prevalence area, and is associated with less aggresive disease than Type I. However, the sequence and structure of these viruses have not been characterized. The complete characterization of a second member (Taiwan-3 isolate) of the Type II HDV from Taiwan is reported. These two Type II HDV isolates (Taiwan-3 and Japan-1) have 93.8% nucleotide homology and 89.3% amino acid homology, respectively. These shared sequences establish the common characteristics of Type II viruses. Sequence comparisons of various HDV genotypes show that the autocatalytic region of the RNA is relatively conserved between Type I and Type II (88.5-95.6% homology) but is significantly divergent in Type III (76.8-80.3% homology). The hypervariable region (nucleotides 1602-658) of RNA, however, is heterogeneous (64.9-73.0%) among all three genotypes. The delta antigen sequence is also very heterogeneous (64.9-73.0%). Most strikingly, the C-terminal sequence (19 amino acids) of the large delta antigen is almost completely different in each of the three genotypes. The heterogeneity in this region of three HDV genotypes may be a basis for their different biological properties, and the nucleotide sequences of this region can be used to differentiate the different genotypes of HDV. The consensus sequence in the four previously identified conserved domains of HDV RNA is defined more precisely.

Adult↗
PubMed1999

Conserved T-cell receptor beta chain CDR3 sequences in IgA nephropathy biopsies.

BACKGROUND: We have previously reported that both alpha beta and gamma delta T cells are involved in the progression of IgA nephropathy (IgAN) to renal failure. To determine whether the T-cells seen in the interstitium represent a generalized inflammatory response or whether they are proliferating oligoclonally in response to a particular antigen, we analyzed the TCR Vbeta gene usage by T cells infiltrating renal biopsies from patients with IgAN. METHODS: Fourteen IgAN patients were divided by clinical criteria into stable and progressive groups (7 in each group). Reverse transcription-polymerase chain reaction (RT-PCR) and cloning were used to characterize the expression of TCR Vbeta families in renal biopsies and in peripheral blood lymphocytes. RESULTS: TCR Vbeta8 was significantly and preferentially expressed in most IgAN kidney biopsies compared with peripheral blood lymphocytes from both IgAN patients and healthy controls (P < 0.001). TCR Vbeta8 expression was more marked in progressive biopsies than in stable biopsies (P < 0.05). Spectratyping of Vbeta8 RT-PCR products from T cells infiltrating the kidney showed an intense spectratype band at the shortest range of amplified CDR3s in the renal biopsies of four patients. Analysis of nucleotide and deduced amino acid sequences of Vbeta8 PCR products derived from intense spectratype bands from these renal biopsies revealed a high concordance across the CDR3 region. A conserved amino acid (leucine) at the first position of the nongermline-encoded nucleotides and diversity (ND) junction of Vbeta8 was found at a frequency of 95% in multiple sequences obtained from the renal biopsies of all four patients examined. CONCLUSIONS: The preferential use of Vbeta8 with marked similarities in the CDR3 region by some renal infiltrating T cells suggests clonal expansion of T cells in the kidneys of some IgAN patients. Conserved amino acids in the TCR CDR3 hypervariable region may contribute to the recognition of a particular antigen or set of antigens.

Adult↗
PubMed2001

Antigenicity and immunogenicity of novel chimeric hepatitis B surface antigen particles with exposed hepatitis C virus epitopes.

The small envelope protein of hepatitis B virus (HBsAg-S) can self-assemble into highly organized virus like particles (VLPs) and induce an effective immune response. In this study, a restriction enzyme site was engineered into the cDNA of HBsAg-S at a position corresponding to the exposed site within the hydrophilic a determinant region (amino acid [aa] 127-128) to create a novel HBsAg vaccine vector allowing surface orientation of the inserted sequence. We inserted sequences of various lengths from hypervariable region 1 (HVR1) of the hepatitis C virus (HCV) E2 protein containing immunodominant epitopes and demonstrated secretion of the recombinant HBsAg VLPs from transfected mammalian cells. A number of different recombinant proteins were synthesized, and HBsAg VLPs containing inserts up to 36 aa were secreted with an efficiency similar to that of wild-type HBsAg. The HVR1 region exposed on the particles retained an antigenic structure similar to that recognized immunologically during natural infection. VLPs containing epitopes from either HCV-1a or -1b strains were produced that induced strain-specific antibody responses in immunized mice. Injection of a combination of these VLPs induced antibodies against both HVR1 epitopes that resulted in higher titers than were achieved by vaccination with the individual VLPs, suggesting a synergistic effect. This may lead to the development of recombinant particles which are able to induce a broad anti-HCV immune response against the HCV quasispecies or other quasispecies-like infectious agents.

Animals↗
PubMed2002

Nucleotide sequence analysis of variable region of VP2 gene of two infectious bursal disease virus isolates from commercial poultry farms.

Two infectious bursal disease virus (IBDV) isolates were obtained from commercial poultry farms with a history of severe outbreaks. A 474-bp product encompassing hypervariable region of IBDV VP2 gene was amplified by reverse transcription-polymerase chain reaction (RT-PCR). The nucleotide sequences of two isolates, VMB1 and VMB2, were determined and compared with those of twenty IBDV strains, including seven very virulent, four classical virulent, four classical attenuated, three antigenic variants and two avirulent serotype 2 strains. The two isolates showed a similarity of 96.5-98.4% with very virulent strains, 84.6-94.6% with classical virulent strains, 90.0-91.4% with classical attenuated strains, 83.0-91.9% with antigenic variants and 65.8-68.7% with avirulent strains. The deduced amino acid sequences of the two isolates showed amino acid substitutions of V256I, N279D, L294I and N299S, specific for very virulent strains. Phylogenetic analysis showed that the two isolates, along with a reported very virulent Indian strain, were closely related to European, Japanese and Chinese very virulent strains indicating their evolutionary origin.

Amino Acid Sequence↗
PubMed1989

Molecular cloning of the Na,K-ATPase alpha-subunit in developing brine shrimp and sequence comparison with higher organisms.

We report here the molecular cloning, nucleotide sequence, and predicted amino acid sequence of an alpha-subunit of the developmentally useful model, Artemia. The amino acid sequence shows divergence from that of mammals, birds, Torpedo, and Drosophila. However, regions in the putative ATP binding and transmembrane domains show absolute or high levels of conservation. Major differences occur in the amino-terminal domain and several other hypervariable regions. These differences are consistent with the suggestion that the brine shrimp is a 'fast clock' organism which diverged from the precursors of vertebrates 0.5-1 billion years ago.

Amino Acid Sequence↗
PubMed1988

Genetic analysis of monoclonal antibody and HIV binding sites on the human lymphocyte antigen CD4.

Saturation mutagenesis and a complement fixation selection have yielded CD4 point mutants with impaired antibody and human immunodeficiency virus binding. The patterns of amino acid substitution, in conjunction with previous antibody cross-blocking data, affirm the similar tertiary structures of the CD4 amino-terminal domain and immunoglobulin variable regions. Single residue substitutions affecting virus binding and syncytium formation are observed over an eight residue segment located in a portion of the molecule homologous to the second hypervariable region of an antibody combining site.

Amino Acid Sequence↗
PubMed1992

An MHC interaction site maps to the amino-terminal half of the T cell receptor alpha chain variable domain.

We have used cloned T cell receptor (TCR) genes from closely related CD4 T cell lines to probe the interaction of the TCR with several specific major histocompatibility complex (MHC) class II ligands. Complementarity determining region 3 (CDR3) equivalents of both alpha and beta TCR chains are required for antigen-MHC recognition. Our data provide novel information about the rotational orientation of TCR-MHC contacts in that exchange of the amino terminal portion of the TCR alpha chain containing the putative CDR1 and CDR2 regions results in both gain and loss of MHC class II specificity by the resulting receptor. These two TCRs differ primarily in recognition of polymorphisms in the second hypervariable region of the MHC class II alpha chain. These results document the involvement of CDR1 and/or CDR2 of the TCR alpha chain in MHC recognition and suggest a rotational orientation of this TCR to its MHC ligand.

Amino Acid Sequence↗
PubMed1990

Structure of miniature swine class II DRB genes: conservation of hypervariable amino acid residues between distantly related mammalian species.

As part of our studies of the class II genes of miniature swine, we have isolated and characterized cDNA clones corresponding to DRB genes from two major histocompatibility complex homozygous strains. Comparison of the sequences of these clones to those of human DRB genes revealed a striking amino acid homology between the hypervariable residues of SLA-DRBc and the human DRB1-0101 allele. The percentage of differences in these residues between the pig DRBc allele and the human DRB1-0101 allele was significantly lower (29%) than that between the DRB1-0101 allele and all other human alleles (average, 66.2%). This similarity was not seen in a comparison of the number of silent substitutions, by which the swine DRBc and the human DRB-0101 differed. Since phenotypic selection operates at the level of protein products rather than nucleotide sequences, these data suggest the existence of selective mechanisms that have resulted in similar hypervariable regions in certain alleles even in these widely disparate species. Consistent with this hypothesis, an examination of available murine and bovine class II sequences revealed a homology in hypervariable residues between the human DRB1-1401 allele and the mouse E beta s allele as well as a cow DRB allele. Consideration of these data along with intraspecies allelic sequence comparisons suggests that at least some of the interspecies similarities have emerged as the result of convergent evolution, possibly as the result of a need to react to common pathogens.

Amino Acid Sequence↗
PubMed1984

Somatic mutation creates diversity in the major group of mouse immunoglobulin kappa light chains.

Using a cloned cDNA of a mouse immunoglobulin kappa light chain synthesized in a myeloma MOPC321 (V kappa-21 subgroup C) as a probe we could detect 13 germ line V kappa gene segments. 11 of these were isolated. Using a set of overlapping cloned segments, we showed that nine of these germ line V kappa genes are arranged in two linkage clusters and that they all have the same transcriptional orientation (11, 12, 22). These two clusters occupy 90 and 30 kb of chromosomal DNA and contain six and three V kappa's, respectively. We determined the complete nucleotide sequences of five germ line V kappa's and showed that three of them encode the prototype sequence of V kappa-21 subgroups B, C, and E. None of these five germ line V kappa's encodes the variant amino acid sequences of known V kappa-21 subgroups. We thus conclude that, as in the lambda 1 light chains, the variant V regions are encoded by gene segments derived by a few somatic mutations from the corresponding germ line DNA. Such somatic mutations are not restricted to sequences encoding the hypervariable regions: they also occur in sequences encoding framework regions.

Amino Acid Sequence↗
PubMed1998

Tracing the origins of louping ill virus by molecular phylogenetic analysis.

The nucleotide and deduced amino acid sequences of louping ill (LI) virus isolates, collected from representative regions of the British Isles and Norway, were determined for either the entire envelope gene (20 isolates) or for a portion of the envelope gene that spans a hypervariable region and includes an LI virus specific marker sequence (53 isolates). Phylogenetic analysis reveals the presence of three major geographical populations of LI virus in the British Isles, viz. Irish, Welsh and British LI viruses, which all cause encephalomyelitis in animals, predominantly sheep, and co-habit the same tick population. British LI virus occurs throughout Scotland, England, Ireland and Norway. Irish and Welsh LI viruses occur only in Ireland and Wales, respectively. Phylogenetic analysis also predicts that LI virus initially emerged in Ireland and that a descendant was introduced into Great Britain via Wales and was subsequently transported to the borders of Scotland, from where it was dispersed throughout Scotland, northern England and Norway. More recently, the British LI virus was reintroduced into Ireland and also into south-west England. Dates of lineage divergence, calculated from the synonymous substitution rate, indicate that LI virus emerged in the British Isles less than 800 years ago and most LI virus dispersal occurred during the last 300 years. By combining these data with historical records it appears that livestock movement can be implicated in the dispersal of LI virus.

Animals↗
PubMed1991

Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens.

To investigate the molecular basis of the autoimmune response to the related i and I carbohydrate antigens, we studied cold agglutinins (CA) from B-cell clones and from the peripheral circulation of patients with lymphoproliferative syndromes. Sequence analyses of expressed variable region genes indicate that both anti-i and anti-I specificities from B-cell clones from two patients are encoded by the VH4.21 or a very closely related VH4 heavy chain gene, whereas the expressed light chain genes differed. The anti-i-secreting B-cells express unmutated germline-encoded VH4.21 and VKI gene sequences. The VH region gene encoding anti-I has the closest homology (97%) to the VH4.21 germline gene and differs at the protein level by only three amino acids. In contrast, while the VL region gene encoding anti-I is most homologous (96%) to the VKIII, kv328 germline gene, there are seven amino acid differences due to nonrandom replacement mutations, which suggests a role for antigen-mediated selection in the anti-I response of this individual. These studies were extended by a structural survey of 20 additional serum CA using antipeptide antibodies specific for determinants in VH and VL regions. All anti-I and anti-i CA were shown to express VH4 heavy chains, and 14 of 17 CA expressed a previously described VH4 second hypervariable region determinant, termed VH4-HV2a. We also found that 13 of 14 anti-I CA used VKIII light chains, while the anti-i CA used light chains from at least three VL families. Taken together, the data show that anti-i and anti-I CA probably both derive from the VH4.21 gene (or a closely related gene). Furthermore, the restricted VH and different VL gene use in anti-i and anti-I CA may reflect the close structural relationship of the i and I antigens.

Autoantibodies↗
PubMed1996

mtDNA variation in the Yanomami: evidence for additional New World founding lineages.

Native Americans have been classified into four founding haplogroups with as many as seven founding lineages based on mtDNA RFLPs and DNA sequence data. mtDNA analysis was completed for 83 Yanomami from eight villages in the Surucucu and Catrimani Plateau regions of Roraima in northwestern Brazil. Samples were typed for 15 polymorphic mtDNA sites (14 RFLP sites and 1 deletion site), and a subset was sequenced for both hypervariable regions of the mitochondrial D-loop. Substantial mitochondrial diversity was detected among the Yanomami, five of seven accepted founding haplotypes and three others were observed. Of the 83 samples, 4 (4.8%) were lineage B1, 1 (1.2%) was lineage B2, 31 (37.4%) were lineage C1, 29 (34.9%) were lineage C2, 2 (2.4%) were lineage D1, 6 (7.2%) were lineage D2, 7 (8.4%) were a haplotype we designated "X6," and 3 (3.6%) were a haplotype we designated "X7." Sequence analysis found 43 haplotypes in 50 samples. B2, X6, and X7 are previously unrecognized mitochondrial founding lineage types of Native Americans. The widespread distribution of these haplotypes in the New World and Asia provides support for declaring these lineages to be New World founding types.

Adult↗
PubMed1978

Sequence variability of immunoglobulins considered from the standpoint of population genetics.

The probability of gene identity between members of a multigene family was investigated, assuming mutation, random genetic drift, and unequal crossing-over. The theoretical results on the equilibrium and transient behavior of the identity probability were applied to the analyses of sequence variability in the variable regions of immunoglobulins. The probability of amino acid identity between corresponding residue sites at different but homologous immunoglobulin sequences was computed both within and between species from data reported by other workers. The average probability of amino acid identity was obtained for the hypervariable regions and also for the framework regions. From statistical analyses based on population genetics theory it is concluded that somatic mutations cannot be the major cause of hypervariability and that the results can readily be explained by the germ line theory.

Journal Article↗
PubMed1998

Organization and evolution of the mitochondrial DNA control region in the avian genus Alectoris.

The entire mitochondrial DNA control region (mtDNA D-loop) was sequenced in the seven extant species of Alectoris partridges. The D-loop length is very conserved (1155 +/- 2 nucleotides), and substitution rates are lower than for the mitochondrial cytochrome b gene of the same species, on average. Comparative analyses suggest that these D-loops can be divided into three domains, corresponding to the highly variable peripheral domains I and III and to the central conserved domain II of vertebrates (Baker and Marshall 1997). Nevertheless, the first 161 nucleotides of domain I of the Alectoris, immediately flanking the tRNAGlu, evolve at an unusually low rate and show motifs similar to the mammalian extended termination-associated sequences [ETAS1 and ETAS2 (Sbisà et al. 1997)], which can form stable secondary structures. The second part of domain I contains a hypervariable region with two divergent copies of a tandemly repeated sequence described previously in other species of anseriforms and galliforms (Quinn and Wilson 1993; Fumihito et al. 1995). Some of the conserved sequence blocks of mammals can be mapped in the central domain of Alectoris. Domain III is highly variable and has sequences similar to mammalian CSB1. The bidirectional transcription promoter HSP/LSP box of the chicken is partially conserved among the Alectoris. This structural organization can be found in the anseriform and galliform species studied so far, suggesting that strong functional constraints might have controlled the evolution of the D-loop since the origin of Galloanserae. Their conserved organization and slow molecular evolution make D-loops of galliforms appropriate for phylogenetic studies, although homoplasy can be be generated at a few hypervariable sites and at some sites which probably have mutated by strand slippage during DNA replication. Phylogenetic analyses of D-loops of Alectoris are concordant with previously published cytochrome b and allozyme phylogenies (Randi 1996). Alectoris is monophyletic and includes three major clades: (1) basal barbara and melanocephala; (2) intermediate rufa and graeca; and (3) recent philbyi, magna, and chukar. Comparative description of the organization and substitution patterns of the mitochondrial control region can aid in mapping hypervariable sites and avoid some sources of homoplasy in data sets which are to be used in phylogenetic analyses.

Animals↗
PubMed2001

Identification of the hexon region of an adenovirus involved in a new outbreak of keratoconjunctivitis.

We tested 15 adenovirus (Ad)-positive patients involved in a case of nosocomial spread of keratoconjunctivitis. A neutralization test, PCR-restriction fragment length polymorphism analysis, and sequencing of the hypervariable regions of the hexons were performed in order to identify the type of Ad involved. The serotype of the Ad was not identical to any published Ad sequence by either method.

Adenovirus Infections, Human↗
PubMed2001

Phylogenetic relationships of aquatic birnaviruses based on deduced amino acid sequences of genome segment A cDNA.

Aquatic birnaviruses, such as infectious pancreatic necrosis virus (IPNV), cause serious diseases in a variety of fish species used worldwide in aquaculture and have also been isolated from a variety of healthy fish and shellfish species. These viruses exhibit a high degree of antigenic heterogeneity and variation in biological properties such as pathogenicity, host range, and temperature of replication. To better understand genetic and biological diversity among these viruses, the nucleotide and deduced amino acid sequences were determined from cDNA of the large open reading frame (ORF) of genome segment A of the 9 type strains of Serogroup A and 4 other representative strains of Serotype A1, the predominant serotype in the United States. In addition, nucleotide and deduced amino acid sequences were determined for the VP2 coding region of a variety of isolates representing 5 of the 9 serotypes. VP2 is the major outer capsid protein of aquatic birnaviruses. RT-PCR was used to amplify a 2904 bp cDNA fragment including all but a few bp of the large ORF of genome segment A or a 1611 bp fragment representing the entire VP2 coding region. Nucleotide and deduced amino acid sequences were determined from the PCR products. Pairwise comparisons were made among our data and 2 other aquatic birnavirus sequences previously published. Several hypervariable regions were identified within the large ORF. The most divergent pair of viruses exhibited a similarity of 80.1% in the deduced amino acid sequence encoded by the large ORF. Genomic relationships revealed in a phylogenetic tree constructed from comparison of the deduced amino acid sequences of the large ORF demonstrated that these viruses were clustered into several genogroups. Phylogenetic comparison of the deduced amino acid sequences of the VP2 coding region of 28 aquatic birnavirus isolates, including the type strains of all 9 serotypes, demonstrated 6 genogroups, some of which were comprised of several genotypes. The most divergent pair of viruses exhibited a similarity of 81.2% in the deduced amino acid sequence from the VP2 coding region. In contrast to previous studies of much shorter genomic sequences within the C-terminus-pVP2/NS junction coding region, these genogroups based on the entire large ORF or the VP2 coding region generally correlated with geographical origin and serological classification. Isolates from the major Canadian serotypes were more closely related to the European isolates than to isolates from the United States.

Amino Acid Sequence↗