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PubMed1988

A molecularly cloned hepatitis B virus produced in vitro is infectious in a chimpanzee.

The infectivity of hepatitis B virus (HBV) produced in vitro by HepG2 cells transfected with HBV DNA (HepG2T14) has been assayed in a chimpanzee. Following inoculation, the chimpanzee underwent a typical course of type B hepatitis infection, characterized by elevation of serum aminotransferases and by histological identification of hepatic damage. Hepatitis B surface antigen and core-related antigen appeared in the serum at weeks 5 and 7, respectively, after infection. HBV DNA was detected in serum samples, and replicative forms of the HBV genome were identified in liver biopsies. Subtype identification of hepatitis B surface antigen and restriction enzyme analysis of HBV DNA in both the inoculum and the serum of the infected chimpanzee confirmed that the hepatitis B infection observed in this animal was caused by viral particles produced by HepG2T14 cells. These findings indicate that, although HepG2 cells do not seem to be susceptible to infection by HBV in vitro, they can produce biologically active infectious virions after transfection with cloned HBV DNA.

Animals↗

PubMed2003

Structure and expression of mobile ETnII retroelements and their coding-competent MusD relatives in the mouse.

ETnII elements are mobile members of the repetitive early transposon family of mouse long terminal repeat (LTR) retroelements and have caused a number of mutations by inserting into genes. ETnII sequences lack retroviral genes, but the recent discovery of related MusD retroviral elements with regions similar to gag, pro, and pol suggests that MusD provides the proteins necessary for ETnII transposition in trans. For this study, we analyzed all ETnII elements in the draft sequence of the C57BL/6J genome and classified them into three subtypes (alpha, beta, and gamma) based on structural differences. We then used database searches and quantitative real-time PCR to determine the copy number and expression of ETnII and MusD elements in various mouse strains. In 7.5-day-old embryos of a mouse strain in which two mutations due to ETnII-beta insertions have been identified (SELH/Bc), we detected a three- to sixfold higher level of ETnII-beta and MusD transcripts than in control strains (C57BL/6J and LM/Bc). The increased ETnII transcription level can in part be attributed to a higher number of ETnII-beta elements, but 70% of the MusD transcripts appear to have been derived from one or a few MusD elements that are not detectable in C57BL/6J mice. This element belongs to a young MusD subgroup with intact open reading frames and identical LTRs, suggesting that the overexpressed element(s) in SELH/Bc mice might provide the proteins for the retrotransposition of ETnII and MusD elements. We also show that ETnII is expressed up to 30-fold more than MusD, which could explain why only ETnII, but not MusD, elements have been positively identified as new insertions.

Animals↗

PubMed2005

APE-type non-LTR retrotransposons: determinants involved in target site recognition.

Non-long terminal repeat (Non-LTR) retrotransposons represent a diverse and widely distributed group of transposable elements and an almost ubiquitous component of eukaryotic genomes that has a major impact on evolution. Their copy number can range from a few to several million and they often make up a significant fraction of the genomes. The members of the dominating subtype of non-LTR retrotransposons code for an endonuclease with homology to apurinic/apyrimidinic endonucleases (APE), and are thus termed APE-type non-LTR retrotransposons. In the last decade both the number of identified non-LTR retrotransposons and our knowledge of biology and evolution of APE-type non-LTR retrotransposons has increased tremendously.

Retroelements↗

PubMedDate not supplied

Prevalence of blood-borne viruses among intravenous drug users and alcoholics in Hiroshima, Japan.

We investigated the prevalence of human immunodeficiency viruses-1 and 2 (HIV-1 and HIV-2), human T-lymphotropic virus type I and II, hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus among intravenous drug users (IVDU) in Hiroshima, Japan, where little is known about their present levels. From June to December 1993, serum samples were collected from 47 IVDU and 98 alcoholics in Hiroshima, Japan, and examined for markers of virus infection. The prevalence of antibody to HCV (anti-HCV) and/or HCV-RNA was significantly higher in IVDU than alcoholics (74.5% vs 20.4%, 44.7% vs 10.2% respectively, P < 0.001). In contrast, the prevalence of antibody to hepatitis B surface antigen and/or core antigen (anti-HBs and/or anti-HBc) showed no significant difference between the 2 groups (57.4% vs 66.3%). HIV-1 infection was found in one (2.1%) IVDU and genome analysis indicated that it was subtype B according to Myers' classification. Thus, an extremely low level of HIV infection and a high level of HCV infection was found in IVDU. Careful follow-up of this group is thought to be needed to minimize an outbreak of HIV-1 infection in Japan.

Adult↗

PubMed2006

Cytomegalovirus and Epstein-Barr virus subtypes--the search for clinical significance.

Cytomegalovirus (CMV) as well as Epstein Barr virus (EBV) genomes include regions which show in part substantial polymorphisms. Characterization of several polymorphic regions led to the identification of various CMV and EBV subtypes. Within the last years there have been undertaken numerous efforts to find out whether the diverse subtypes differentially contribute to clinical manifestations. However, although some associations have been described so far between a certain virus subtype and the development of individual diseases these analyses were greatly complicated by the huge genomic background of CMV and EBV, by the large variety of individual host-virus relations and by differences in the geographic or demographic subtype distribution. In addition, it was shown meanwhile that a substantial proportion of virus infections is due to mixed infections with different subtypes. In this review we will give an overview of the current knowledge concerning the clinical significance of individual CMV and EBV subtypes, defined by characterization of selected polymorphisms. In addition, we also focus on recent analyses which show that infection with mixed virus subtype populations may be disadvantageous compared to single virus subtype infections.

Cytomegalovirus↗

PubMed2007

Epidemic dynamics of two coexisting hepatitis C virus subtypes.

Hepatitis C virus (HCV) infection affects about 3% of the human population. Phylogenetic analyses have grouped its variants into six major genotypes, which have a star-like distribution and several minor subtypes. The most abundant genotype in Europe is the so-called genotype 1, with two prevalent subtypes, 1a and 1b. In order to explain the higher prevalence of subtype 1b over 1a, a large-scale sequence analysis (100 virus clones) has been carried out over 25 patients of both subtypes in two regions of the HCV genome: one comprising hypervariable region 1 and another including the interferon sensitivity-determining region. Neither polymorphism analysis nor molecular variance analysis (attending to intra- and intersubtype differences, age, sex and previous history of antiviral treatment) was able to show any particular difference between subtypes that might account for their different prevalence. Only the demographic history of the populations carrying both subtypes and analysis of molecular variance (AMOVA) for risk practice suggested that the route of transmission may be the most important factor to explain the observed difference.

Analysis of Variance↗

PubMed2006

Mucinous colorectal cancers with chromosomal instability: a biologically distinct and aggressive subtype.

Colorectal cancers can progress through 2 pathways of genomic instability: microsatellite instability (MSI) and chromosomal instability (CSI). We investigated the influence of CSI and MSI on clinicopathological features and survival of 35 patients affected by mucinous colorectal cancers (MCRC). MSI status was determined by PCR amplification using 5 standard markers. Evidence for CSI was gathered by identifying loss of heterozygosity (LOH) of 4 loci (2p, 5q, 17p, 18q). We defined "MSI-MCRC" as those that showed MSI-H, and "CSI-MCRC" as those that showed LOH at 1 or more of these sites but did not show MSI-H. Among 35 cases, 18 cases (51.4%) were CSI-MCRC, whereas 11 cases (31.4%) were MSI-MCRC. Significant differences were found between CSI-MCRC and MSI-MCRC regarding the following clinicopathological features: tumor location (P=0.00026), lymph node metastasis (P=0.026), and TNM stage (P=0.026). Kaplan-Meier survival curves and log-rank analysis demonstrated that MSI-MCRC was associated with better prognosis than CSI-MCRC, although no significant difference was found (P=0.10). CSI-MCRC correlates more strongly with lymph node metastasis and advanced stage than MSI-MCRC. This indicates that CSI-MCRC is an aggressive subtype.

Adenocarcinoma, Mucinous↗

PubMedDate not supplied

Analysis of the genome structure of influenza A virus strains isolated during the epidemics of 1977-1980.

The genome structure of different A(H1N1) and A(H3N2) influenza virus strains isolated from 1977 to 1980 was analysed by electrophoresis of single-stranded RNA and of the double-stranded RNA obtained by hybridization with complementary RNA of the A/Stavropol 188/79 (H3N2) strain. The differences in genome structure are insignificant within the A(H1N1) subtype, and considerable (involving almost all the 8 RNA fragments) between the two A(H3N2) strains (A/Texas 1/77 and A/Stavropol 188/79). The great differences between the genomes of A(H1N1) and A(H3N2) strains do not exclude certain genetic relationships between these viruses.

Base Sequence↗

PubMed1992

Human gene S31 encodes the pharmacologically defined serotonin 5-hydroxytryptamine1E receptor.

The gene encoding a human 5-hydroxytryptamine (5-HT)1 receptor subtype was isolated from a human placental genomic library by using oligonucleotide probes derived from transmembrane regions of the cloned human 5-HT1D beta receptor. The deduced amino acid sequence of the genomic clone hp75d is identical to that of the recently isolated, but uncharacterized, novel serotonin receptor gene S31. Transmembrane domain sequence comparison of clone hp75d with other guanine nucleotide-binding protein-coupled receptors revealed the highest degree of homology (64%) to the 5-HT1D alpha and 5-HT1D beta subtypes and lower degrees of homology (35-52%) to other serotonergic and catecholaminergic receptors. A stable cell line expressing this gene was established, using murine fibroblasts as the host cell, for pharmacological evaluation. High affinity (Kd = 9.7 nM), saturable (Bmax = 2.4 pmol/mg of protein) [3H]5-HT binding was detected using membranes derived from stable transfectants. Most compounds displayed low affinity (K(i) greater than 200 nM) for the expressed gene, with the exception of 5-HT (K(i) = 10 nM). The rank order of potency of ligands to compete for the [3H]5-HT-labeled site best matched the binding profile of the pharmacologically defined 5-HT1E binding site, 5-HT greater than methysergide greater than ergotamine greater than 8-hydroxy-2-(di-n-propylamino)tetralin greater than 5-carboxyamidotryptamine greater than ketanserin. 5'-Guanylylimidodiphosphate decreased high affinity agonist ([3H]5-HT) binding in a dose-dependent manner. 5-HT produced a dose-dependent inhibition of forskolin-stimulated cAMP accumulation in intact cells stably expressing the 5-HT1E gene. The response was blocked by the nonselective 5-HT1 receptor antagonist methiothepin. The molecular biological and pharmacological data are consistent with the designation that clone hp75d encodes a functional 5-HT1E receptor.

Adenylyl Cyclases↗

PubMed2006

Genome comparison in silico in Neisseria suggests integration of filamentous bacteriophages by their own transposase.

We have identified filamentous prophages, Nf (Neisserial filamentous phages), during an in silico genome comparison in Neisseria. Comparison of three genomes of Neisseria meningitidis and one of Neisseria gonorrhoeae revealed four subtypes of Nf. Eleven intact copies are located at different loci in the four genomes. Each intact copy of Nf is flanked by duplication of 5'-CT and, at its right end, carries a transposase homologue (pivNM/irg) of RNaseH/Retroviral integrase superfamily. The phylogeny of these putative transposases and that of phage-related proteins on Nfs are congruent. Following circularization of Nfs, a promoter-like sequence forms. The sequence at the junction of these predicted circular forms (5'-atCTtatat) was found in a related plasmid (pMU1) at a corresponding locus. Several structural variants of Nfs--partially inverted, internally deleted and truncated--were also identified. The partial inversion seems to be a product of site-specific recombination between two 5'-CTtat sequences that are in inverse orientation, one at its end and the other upstream of pivNM/irg. Formation of internally deleted variants probably proceeded through replicative transposition that also involved two 5'-CTtat sequences. We concluded that the PivNM/Irg transposase on Nfs integrated their circular forms into the chromosomal 5'-CT-containing sequences and probably mediated the above rearrangements.

Base Sequence↗

PubMed1997

Evolution of human immunodeficiency virus subtype A in women seroconverting post partum and in their offspring post-natally infected by ingestion of breast milk.

The evolution of genomic RNA of human immunodeficiency virus type 1 (HIV-1), subtype A, was studied in three Rwandan mother-child pairs over a period of 12-30 months. In two pairs a homogeneous subtype A V3 sequence population was observed at seroconversion and the virus populations in the children resembled those in the mothers. One of these mother-child pairs was infected with an A/C recombinant virus (Ap17/Cp24). In the third pair, a heterogeneous V3 sequence population was observed in the maternal seroconversion sample but the V3 sequence population in the child's sample was homogeneous. In each individual the intra- and intersample variation (between the seroconversion and follow-up samples) increased over time in both the V3 region and p17gag. Independent evolution for 1-2 years did not abolish the epidemiological relationship between virus populations in mother and child.

Amino Acid Sequence↗

PubMed2001

Human immunodeficiency virus type 1 reverse-transcriptase and protease subtypes: classification, amino acid mutation patterns, and prevalence in a northern California clinic-based population.

Phylogenetic analysis of the reverse transcriptase (RT) and protease of 117 published complete human immunodeficiency virus (HIV) type 1 genome sequences demonstrated that these genes cluster into distinct subtypes. There was a slightly higher proportion of informative sites in the RT (40.4%) than in the protease (34.8%; P= .03). Although most variation between subtypes was due to synonymous nucleotide substitutions, several subtype-specific amino acid patterns were observed. In the protease, the subtype-specific variants included 7 positions associated with drug resistance. Variants at positions 10, 20, 36, and 82 were more common in non-B isolates, whereas variants at positions 63, 77, and 93 were more common in subtype B isolates. In the RT, the subtype-specific mutations did not include positions associated with anti-retroviral drug resistance. RT and protease sequences from 2246 HIV-infected persons in northern California were also examined: 99.4% of the sequences clustered with subtype B, whereas 0.6% clustered with subtype A, C, or D.

Amino Acid Sequence↗

PubMed2001

Hepatitis C virus genotyping: clinical implications and methods.

Hepatitis C virus (HCV) chronically infects at least 1% of the world's population and is a leading cause of end-stage liver disease. HCV displays a remarkable degree of genomic diversity, with the six major genotypes and numerous subtypes differing in geographic distribution. The ability of this virus to cause persistent infections is a direct result of its genomic plasticity and the evolution of quasispecies within an infected individual. HCV genotype has emerged as an important factor both in predicting a sustained response to, and in determining the duration of, antiviral therapy. Although a variety of methods have been used for genotyping HCV, nucleotide sequencing of a phylogenetically informative region remains the gold standard.

Animals↗

PubMed2002

Parallel analysis of sporadic primary ovarian carcinomas by spectral karyotyping, comparative genomic hybridization, and expression microarrays.

Analysis of ovarian carcinomas has shown that karyotypes are often highly abnormal and cannot be identified with certainty by conventional cytogenetic methods. In this study, 17 tumors derived from 13 patients were analyzed by a combination of spectral karyotyping (SKY), comparative genomic hybridization (CGH), and expression microarrays. Within the study group, a total of 396 chromosomal rearrangements could be identified by SKY and CGH analysis. When the distribution of aberrations was normalized with respect to relative genomic length, chromosomes 3, 8, 11, 17, and 21 had the highest frequencies. Parallel microarray expression studies of 1718 human cDNAs were used to analyze expression profiles and to determine whether correlating gene expression with chromosomal rearrangement would identify smaller subsets of differentially expressed genes. Within the entire set of samples, microarray expression analysis grouped together poorly differentiated tumors irrespective of histological subtype. For three patients, a comparison between genomic alterations and gene expression pattern was performed on samples of primary and metastatic tumors. Their common origin was demonstrated by the close relationship of both the SKY and CGH karyotypes and the observed profiles of gene expression. In agreement with the pattern of genomic imbalance observed for chromosome 3 in ovarian cancer, the relative expression profile with respect to a normal ovary exhibited a contiguous pattern of reduced expression of genes mapping to the 3p25.5-3p21.31 and increased expression of genes from 3q13.33-3q28. This study demonstrates that SKY, CGH, and microarray analysis can in combination identify significantly smaller subsets of differentially expressed genes for future studies.

Adult↗

PubMed1996

Human immunodeficiency virus type 1 subtypes defined by env show high frequency of recombinant gag genes. The UNAIDS Network for HIV Isolation and Characterization.

Genetic subtypes of human immunodeficiency virus type 1 can be distinguished on the basis of phylogenetic analysis of their envelope (env) gene. A significant proportion of human immunodeficiency virus type 1 strains was retrospectively shown to result from recombination events between viruses belonging genetically to distinct subtypes (D. L. Robertson, P. M. Sharp, F. E. McCutchan, and B. H. Hahn, Nature [London] 374:124-126, 1995). To establish the frequency of natural infections with recombinant viruses and to exclude tissue culture artifacts, we analyzed plasma samples from the UNAIDS sample collection. The collection includes samples from 53 individuals infected with subtype A (n = 9), subtype B (n = 15), subtype C (n = 1), subtype D (n = 13), and subtype E (n = 15) on the basis of V3 region analysis. Phylogenetic analysis of the gag gene fragment showed intersubtype recombinant genomes in 23 cases: 3 of 9 (33%) of subtype A, 2 of 15 (13%) of subtype B, 3 of 13 (23%) of subtype D, and all of subtype E. Of the 23 recombinant viruses, 19 had a gag gene from one subtype and env from another (B(env)/C(gag), A(env)/C(gag), D(env)/A(gag), and E(env)/A(gag)). Phylogenetic analysis clustered the A(gag) of subtype E viruses as an outgroup of subtype A, suggesting that these viruses may belong to a distinct A' cluster. The remaining four recombinant viruses (B(env)/B(p17)F(p24), A(env)/A(p17)D(p24), A(env)/A(p17)C(p24), and D(env)/ D(p17)A(p24)) had breakpoint crossover sites in the proximity of the p17-p24 protein processing site. We conclude that recombination in the gag gene is highly frequent among the major env subtypes and that selection of recombinants is apparently based on particularly beneficial combinations of gag and env gene products.

Gene Frequency↗

PubMed1990

Major histocompatibility complex class I genes of Peromyscus leucopus.

Class I genes of the Peromyscus leucopus major histocompatibility complex (MhcPele) were examined by Southern blot hybridization, genomic cloning, and DNA sequencing. At least three distinct subtypes of Pele class I genes were discerned, which we have designated Pele-A, B, and C. The nucleotide sequences of exon 5-containing regions (encoding the transmembrane domain) suggested that Pele-A genes are homologs of mouse H-2K, D, L, and Q genes and that Pele-B genes correspond to mouse Tla genes. The Pele-C genes appeared similar to mouse M1 genes. The number of unique genes in each subtype cloned from an individual P. leucopus were 20 for Pele-A, 13 for Pele-B, and 2 for Pele-C. Three genomic clones showed cross-hybridization to both Pele-A and Pele-B gene-specific probes. Six genomic clones remained unclassified as they did not cross-hybridize to exon 5-containing probes from Pele-A, B, or C genes. The homology between the transmembrane domains of Pele class I gene subtypes was found to be similar to that observed between the transmembrane domains of H-2 subtypes (or groups). Interspecific similarity of exon 5 was found to be 81%-88% between Pele class I genes and their H-2 counterparts.

Animals↗

PubMed1993

Typing of Staphylococcus aureus by pulsed-field gel electrophoresis, zymotyping, capsular typing, and phage typing: resolution of clonal relationships.

Sixty-nine Staphylococcus aureus isolates from two epidemiologically unrelated sources were typed by pulsed-field gel electrophoresis after SmaI digestion of chromosomal DNA (genome typing), and the results were compared with those obtained by other typing methods: phage typing with the international set of phages, capsular serotyping with monoclonal antibodies against capsular polysaccharides type 5 and 8, and zymotyping by polyacrylamide agarose electrophoresis for esterase polymorphism. A good correlation of S. aureus types was found by these four typing methods. Differentiation increased in the order capsular typing < zymotyping < phage typing < genome typing, yielding 2, 10, 20, and 26 different S. aureus types, respectively. Five of the 26 genome types were further divided into several subtypes revealing clonal relationships. When 36 French S. aureus isolates were compared with 33 German S. aureus isolates, 3 strains representing clonal populations were identical in both groups. S. aureus isolates from patients with cystic fibrosis were also typed at the beginning and the end of a 4-week summer camp for these patients. The results suggested a possible strain transmission during the summer camp. We conclude that genome typing by pulsed-field gel electrophoresis is a powerful tool not only for strain identification but also for the resolution of the clonal relationships of S. aureus strains.

Bacterial Typing Techniques↗

PubMed2003

Near full-length genomes of 15 HIV type 1 group O isolates.

Human immunodeficiency virus type 1 (HIV-1) is classified into three distinct groups; M (major), N (non-M/non-O), and O (outlier). Group M strains are further subclassified into subtypes, subsubtypes, and circulating recombinant forms (CRF). While the level of genetic diversity within group O is similar to that between group M subtypes, group O has not been classified into subtypes. A previous study, based on the phylogenetic analyses of the gag p24, pol p32, and env gp160 sequences from 39 group O isolates, laid the foundation for the classification of group O subtypes. Five phylogenetic clusters, I-V, were identified that have characteristics analogous to group M subtypes. However, a complete phylogenetic analysis and classification of group O requires the availability of at least two full-length and one partial genomes for each group O phylogenetic cluster. In this study, 15 group O isolates were selected for full genome sequencing. Phylogenetic analysis of the 15 sequences with eight additional group O genomes supports the classification of three group O subtypes (I-III) and the potential existence of one CRF (IV) and at least one additional subtype (V). The group O subtypes are equidistant to each other and lack subsegments of other subtypes. The intra- and intersubtype genetic distances for group O are similar in magnitude to the corresponding distances for group M subtypes. Intersubtype recombination was identified in three of the 23 (13%) group O genomes. Formal classification of group O subtypes should be forthcoming pending the analysis of additional group O genomes and agreement of the HIV nomenclature committee.

Drug Resistance, Viral↗