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PubMed2004

Patterns of chromosomal alterations in breast ductal carcinoma in situ.

PURPOSE: Ductal carcinoma in situ (DCIS) is thought to be a nonobligate precursor of invasive cancer. Genomic changes specific to pure DCIS versus invasive cancer, as well as alterations unique to individual DCIS subtypes, have not been fully defined. EXPERIMENTAL DESIGN: Chromosomal copy number alterations were examined by comparative genomic hybridization in 34 cases of pure DCIS and compared with 12 cases of paired synchronous DCIS and invasive ductal cancer, as well as to 146 additional cases of invasive breast cancer of ductal or lobular histology. Genomic differences between high-grade and low/intermediate-grade DCIS, as well as between pure DCIS and invasive cancer, were identified. RESULTS: Pure DCIS showed almost the same degree of chromosomal instability as invasive ductal cancers. A higher proportion of low/intermediate-grade versus high-grade DCIS had loss of 16q (65 versus 12%, respectively; P = 0.002). When compared with lower grade DCIS, high-grade DCIS exhibited more frequent gain of 17q (65 versus 41%; P = 0.15) and higher frequency loss of 8p (77 versus 41%; P = 0.04). Chromosomal alterations in those cases with synchronous DCIS and invasive ductal cancer showed a high degree of shared changes within the two components. CONCLUSIONS: DCIS is genetically advanced, showing a similar degree of chromosomal alterations as invasive ductal cancer. The pattern of alterations differed between high- and low/intermediate-grade DCIS, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes. These regions of chromosomal alterations may be potential targets for treatment and/or markers of prognosis.

Adult↗

PubMed1990

Nucleotide sequence of the genome and complete amino acid sequence of the polyprotein of tick-borne encephalitis virus.

The sequence of the genome of tick-borne encephalitis (TBE) virus (Far Eastern subtype, strain Sofjin) coding for structural proteins and nonstructural protein NS1 has been previously reported (A. G. Pletnev, V. F. Yamshchikov, and V. M. Blinov, 1986, FEBS Lett. 200, 317-321; Yamshchikov and Pletnev, 1988, Nucleic Acids Res. 16, 7750. Now we have cloned and sequenced the genomic RNA that encodes all nonstructural proteins. Together with our earlier sequence analyses, these data show that the TBE genome is 10,477 bases in length with a single open reading frame extending from nucleotides 127 to 10,363, encoding 3412 amino acids. The 5'- and 3'-noncoding regions have stem-loop structures. The polyprotein precursor is proteolytically cleaved, apparently by a mechanism resembling that proposed for the expression of polyproteins of the other flaviviruses, such as yellow fever and Kunjin viruses. The deduced TBE gene order is 5'-C-pre(M)M-E-NS1-NS2A-NS2B-NS3-ns4a-NS4B -NS5-3'. The genome structure and the polyprotein of TBE virus is similar to mosquito-borne flaviviruses, although TBE virus is transmitted by ticks. Comparison of the sequence homology of polyproteins of flaviviruses suggests that TBE virus is more closely related to yellow fever virus than to other serological subgroups of flaviviruses. The hydrophobicity profile of the TBE polyprotein is similar to those of other flaviviruses. Nonstructural proteins NS2A, NS2B, ns4a, and NS4B are extremely hydrophobic, suggesting that these proteins are likely associated with cellular membranes. Proteins E, NS1, NS3, and NS5 are the most conserved and these proteins may be involved in the general activities related to viral reproduction.

Amino Acid Sequence↗

PubMed1989

Structural analysis of human papillomavirus type 6c isolates from condyloma acuminatum and juvenile-onset and adult-onset laryngeal papillomata.

The human papillomavirus type 6c (HPV-6c) genome was molecularly cloned from biopsy specimens of a juvenile-onset and an adult-onset respiratory-tract papillomata and a condyloma acuminatum of the cervix. To determine if the genital-tract isolate and respiratory-tract isolates contain divergent sequences that may account for a difference in tissue trophism or for a difference in the age of onset of the disease, fine-structure mapping, heteroduplex analysis by electron microscopy, and nucleotide sequencing were used to examine the sequence relationship among these HPV-6c isolates. No differences were found in the digestion patterns with 23 restriction enzymes. Heteroduplex analysis among the three genomes demonstrated that they were colinear without apparent deletions or rearrangements and had greater than 90% sequence identity. In heteroduplex analyses with a different subtype (HPV-6e) that was molecularly cloned from a genital wart, the genomes were colinear with greater than 90% sequence identity over 90% of their length. The most divergent region had 75-80% sequence identity and was localized to the part of the genome containing the E5a and E5b open reading frames (ORFs). Comparison of the sequence of 1430 nucleotides in this region for two of the HPV-6c isolates did not identify any differences between them. Comparison with the published sequences of HPV-6b identified deletions/insertions and base changes with approximately 75% sequence identity, and comparison with HPV-11 identified only six base changes. Conservation of sequences in the E4-E5 region and similarity in the restriction enzyme maps demonstrated that HPV-6c and HPV-11 are independent isolates of the same HPV-6 subtype.

Base Sequence↗

PubMed2006

Differential disruption of cell cycle pathways in small cell and non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality in the world, with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) comprising the two major cell types. Although these cell types can be distinguished readily at the histological level, knowledge of their underlying molecular differences is very limited. In this study, we compared 14 SCLC cell lines against 27 NSCLC cell lines using an integrated array comparative genomic hybridisation and gene expression profiling approach to identify subtype-specific disruptions. Using stringent criteria, we have identified 159 of the genes that are responsible for the different biology of these cell types. Sorting of these genes by their biological functions revealed the differential disruption of key components involved in cell cycle pathways. Our novel comparative combined genome and transcriptome analysis not only identified differentially altered genes, but also revealed that certain shared pathways are preferentially disrupted at different steps in these cell types. Small cell lung cancer exhibited increased expression of MRP5, activation of Wnt pathway inhibitors, and upregulation of p38 MAPK activating genes, while NSCLC showed downregulation of CDKN2A, and upregulation of MAPK9 and EGFR. This information suggests that cell cycle upregulation in SCLC and NSCLC occurs through drastically different mechanisms, highlighting the need for differential molecular target selection in the treatment of these cancers.

Carcinoma, Non-Small-Cell Lung↗

PubMedDate not supplied

[The determination of the genotype of natural reassortant influenza A viruses according to the core protein genes by the methods of competitive dot hybridization and sequencing].

Simultaneous circulation of different subtypes of influenza A viruses provides conditions for reassortant strains formation. A comparative investigation of genome of 47 influenza A virus strains (H1N1, H2N2, and H3N2) was carried out by competitive dot hybridization technique and sequence analysis of some of cDNA-copies of the virus genes. All the genes of 43 strains encoding nonglycolysed proteins corresponded to the serum subtype of surface glycoproteins. The reassortant pattern of genome for some genes of core proteins was revealed in 4 viruses. All the dot hybridization data were completely confirmed by sequence analysis of the genes.

Antigens, Viral↗

PubMed2026

Diversified cell origin of Helicobacter pylori eradication-responsive gastric diffuse large B-cell lymphomas.

A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT ('pure' DLBCL) can be resolved by Helicobacter pylori eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 'pure' DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 'pure' DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with 'pure' DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and BCL2 rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric 'pure' DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with 'Hans' GCB had GCB genetic signatures, whereas four of five patients with 'Hans' non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with 'Hans' GCB. The expression patterns of BACH2 (p = 0.005) and AID (p = 0.038) closely correlated with the 'Hans' GCB phenotype. BCL2 rearrangements and EZH2 codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with 'Hans' GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 'pure' DLBCLs and 10 DLBCL(MALT)s], we found a close association between the 'Hans' GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.

Humans↗

PubMed1983

DNA structure, and hemagglutination properties of bovine adenovirus type 2 strains which bypass species specificity.

Bovine adenovirus type 2 (Ad bos 2) strains were examined which had been isolated during natural outbreaks among calves, and lambs in Hungary [Belák, S., Pálfi, V.: Arch. ges. Virusforsch. 46,366-369 (1974)]. Differences were detected in hemagglutination properties, and in the restriction site maps of the DNA, which seem to be sufficient to group isolates of Ad bos 2 into two subtypes (subspecies). Some of the strains, recovered from cattle including prototype strain No. 19 are suggested to be separated as subtype A. These viruses hemagglutinate bovine red blood cells, and the physical map of the DNA is similar to, or identical with that of the prototype strain. Virus strains tentatively grouped into subtype B are pathogenic for both cattle, and sheep under natural conditions. Members of subtype B hemagglutinate only rat erythrocytes, and characteristic differences may be detected with BamHI, EcoRI, KpnI, and SalI restriction endonucleases in comparison to the physical maps of the DNA of prototype virus. The genome size of all isolates tested was measured to be of Mr 19.5 to 20.0 X 10(6), similar to Ad ovi 1, 4, and Ad bos 4, and 6. All isolates of subtype B characteristics were shown to encapsidate heterogeneous genome populations which could be distinguished from those of subtype A by the presence of specific restriction endonuclease cleavage fragments with molar ratios of less than 1.0.

Adenoviridae↗

PubMed2006

Genomic diversity in the regulatory nef gene sequences in Indian isolates of HIV type 1: emergence of a distinct subclade and predicted implications.

The regulatory functional nef gene is known to mediate a cascade of events during pathogenesis in HIV infection. Variability in the nef gene sequences of HIV-1 A and B subtypes has been well documented. Reasonable data are also available on the pattern of genomic changes in the nef gene of African strains of HIV-1 subtype C, but very little is known about heterogeneity in the nef gene of Indian strains of HIV-1 subtype C, which accounts for 90% of the estimated 5.2 million cases of HIV infection in India. This is a huge number and, therefore, it is important to reveal the extent of sequence variability in the nef gene of HIV-1 subtypes circulating in different parts of India. We carried out full-length nef gene (approximately 620 bp) sequencing on a large number of clinical isolates of HIV-1 circulating in different geographic regions of India. Comparative and phylogenetic analysis revealed 88% (38/43) of cases was HIV-1 subtype C; four cases were diagnosed as subtype A and only one as subtype B. Although most of the crucial functional motifs of the nef gene were conserved, we did observe a few important variations in juxtapositions to functional domains. Interestingly, analyzed nef sequences showed an evolving pattern of segregation away from those reported from other parts of the world, to form a distinct Indian subclade. Deduced amino acid (aa) sequences used to predict HLA binding epitopes for consensus nef gene sequences of Indian strains of HIV-1 revealed two HLA subtype binding domains, GAFDLSFFL (at aa 83) and LTFGWCFKL (at aa 136), in high frequency. The findings from the present study may encourage use of nef gene in molecular diagnostics/genotyping, keeping track of the evolutionary trend and pinpointing the emergence of recombinant strains, and in the future, designing a multiepitope HIV vaccine suitable for the Indian population.

Adolescent↗

PubMed2001

Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course.

Sixty-four patients with adult T-cell leukemia/lymphoma (ATL; 18 patients with indolent subtype and 46 with aggressive subtype) associated with human T-lymphotropic virus type 1 (HTLV-1) were analyzed using comparative genomic hybridization (CGH). The most frequent observations were gains at chromosomes 14q, 7q, and 3p and losses at chromosomes 6q and 13q. Chromosome imbalances, losses, and gains were more frequently observed in aggressive ATL than in indolent ATL, with significant differences between the 2 ATL subtypes at gains of 1q and 4q. An increased number of chromosomal imbalances was associated with a significantly shorter survival in all patients. A high number of chromosomal losses was associated with a poor prognosis in indolent ATL, whereas the presence of 7q+ was marginally associated with a good prognosis in aggressive ATL. Paired samples (ie, samples obtained at different sites from 4 patients) and sequential samples from 13 patients (from 6 during both chronic disease and acute crisis and from 7 during both acute onset and relapse) were examined by CGH and Southern blotting for HTLV-1. All but 2 paired samples showed differences on CGH assessment. Two chronic/crisis samples showed distinct results regarding both CGH and HTLV-1 integration sites, indicating clonal changes in ATL at crisis. In 11 patients, the finding of identical HTLV-1 sites and clonally related CGH results suggested a common origin of sequential samples. In contrast to chronic/crisis samples, CGH results with all acute/relapse sample pairs showed the presence of clonally related but not evolutional subclones at relapse, thereby suggesting marked chromosomal instability. In summary, clonal diversity is common during progression of ATL, and CGH alterations are associated with clinical course. (Blood. 2001;97:3875-3881)

Adult↗

PubMed2004

Multigene family for Bowman-Birk type proteinase inhibitors of wild soja and soybean: the presence of two BBI-A genes and pseudogenes.

Genes for Bowman-Birk type protease inhibitors (BBIs) of wild soja (Glycine soja) and soybean (Glycine max) comprise a multigene family. The organization of the genes for wild soja BBIs (wBBIs) was elucidated by an analysis of their cDNAs and the corresponding genomic sequences, and compared with the counterparts in the soybean. The cDNAs encoding three types of wild soja BBIs (wBBI-A, -C, and -D) were cloned. Two subtypes of cDNAs for wBBI-A, designated wBBI-A1 and -A2, were further identified. Similar subtypes (sBBI-A1 and -A2) were also found in the soybean genome. cDNA sequences for wBBIs were highly homologous to those for the respective soybean homologs. Phylogenetic analysis of these cDNAs demonstrated the evolutional proximity between these two leguminae strains.

Base Sequence↗

PubMed2001

Chromosomal imbalances in gastric cancer. Correlation with histologic subtypes and tumor progression.

DNA copy number changes were analyzed by comparative genomic hybridization (CGH) in 38 gastric carcinomas and correlated with tumor histologic type and progression. Gains of copy numbers were observed in all tumors, affecting all chromosomes except chromosome 16. The average number of copy number gains was 7 (range, 1-13), most frequently located on chromosomes 11, 12, 15, 17, and 20 in 45% to 97% of tumors. High-level amplifications were found on chromosomes 12, 15, 17, and 20; the latter was affected most frequently (66%). Loss of DNA copy numbers was detected in 14 tumors affecting 7 chromosomes. No statistically significant differences in the frequency and pattern of chromosomal imbalances were observed in tumor histologic type (Lauren classification) and grade of differentiation, as well as the prognostic parameters depth of invasion (pT) and lymph node involvement (pN). Our results indicate that in gastric cancer there is no specific recurrent pattern of DNA aberrations to be correlated with tumor histologic type or stage. However, CGH analysis could reveal new, recurrent genetic changes in gastric cancer affecting chromosomes sites that harbor genes known to participate in tumorigenesis and progression of several human malignant neoplasms.

Carcinoma↗

PubMed2004

Variation in RNA expression and genomic DNA content acquired during cell culture.

Specific chromosomal abnormalities are increasingly recognised to be associated with particular tumour subtypes. These cytogenetic abnormalities define the sites of specific genes, the alteration of which is implicated in the neoplastic process. We used comparative genomic hybridisation (CGH) to examine DNA from different breast and ovarian cancer cell lines for variations in DNA sequence copy number compared with the same normal control. We also compared different sources of the MCF7 breast line by both CGH and cDNA expression arrays. Some of the differences between the subcultures were extensive and involved large regions of the chromosome. Differences between the four subcultures were observed for gains of 2q, 5p, 5q, 6q, 7p, 7q, 9q, 10p, 11q, 13q, 14q, 16q, 18p and 20p, and losses of 4q, 5p, 5q, 6q, 7q, 8p, 11p, 11q, 12q, 13q, 15q, 19p, 19q, 20p, 21q, 22q and Xp. However, few variations were found between two subcultures examined, 5 months apart, from the same initial source. The RNA arrays also demonstrated considerable variation between the three different subcultures, with only 43% of genes expressed at the same levels in all three. Moreover, the patterns of the expressed genes did not always reflect our observed CGH aberrations. These results demonstrate extensive genomic instability and variation in RNA expression during subculture and provide supportive data for evidence that cell lines do evolve in culture, thereby weakening the direct relevance of such cultures as models of human cancer. This work also reinforces the concern that comparisons of published analyses of cultures of the same name may be dangerous.

Breast Neoplasms↗

PubMed2005

Highly diverse variable number tandem repeat loci in the E. coli O157:H7 and O55:H7 genomes for high-resolution molecular typing.

AIM: Evaluation of the Escherichia coli genome for variable number tandem repeat (VNTR) loci in order to provide a subtyping tool with greater discrimination and more efficient capacity. METHODS AND RESULTS: Twenty-nine putative VNTR loci were identified from the E. coli genomic sequence. Their variability was validated by characterizing the number of repeats at each locus in a set of 56 E. coli O157:H7/HN and O55:H7 isolates. An optimized multiplex assay system was developed to facility high capacity analysis. Locus diversity values ranged from 0.23 to 0.95 while the number of alleles ranged from two to 29. This multiple-locus VNTR analysis (MLVA) data was used to describe genetic relationships among these isolates and was compared with PFGE (pulse field gel electrophoresis) data from a subset of the same strains. Genetic similarity values were highly correlated between the two approaches, through MLVA was capable of discrimination amongst closely related isolates when PFGE similar values were equal to 1.0. CONCLUSIONS: Highly variable VNTR loci exist in the E. coli O157:H7 genome and are excellent estimators of genetic relationships, in particular for closely related isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: Escherichia coli O157:H7 MLVA offers a complimentary analysis to the more traditional PFGE approach. Application of MLVA to an outbreak cluster could generate superior molecular epidemiology and result in a more effective public health response.

Alleles↗

PubMed2006

Stochastic processes are key determinants of short-term evolution in influenza a virus.

Understanding the evolutionary dynamics of influenza A virus is central to its surveillance and control. While immune-driven antigenic drift is a key determinant of viral evolution across epidemic seasons, the evolutionary processes shaping influenza virus diversity within seasons are less clear. Here we show with a phylogenetic analysis of 413 complete genomes of human H3N2 influenza A viruses collected between 1997 and 2005 from New York State, United States, that genetic diversity is both abundant and largely generated through the seasonal importation of multiple divergent clades of the same subtype. These clades cocirculated within New York State, allowing frequent reassortment and generating genome-wide diversity. However, relatively low levels of positive selection and genetic diversity were observed at amino acid sites considered important in antigenic drift. These results indicate that adaptive evolution occurs only sporadically in influenza A virus; rather, the stochastic processes of viral migration and clade reassortment play a vital role in shaping short-term evolutionary dynamics. Thus, predicting future patterns of influenza virus evolution for vaccine strain selection is inherently complex and requires intensive surveillance, whole-genome sequencing, and phenotypic analysis.

Antigenic Variation↗

PubMed2006

Distribution of human T cell lymphotropic virus type 1 (HTLV-1) subtypes in Brazil: genetic characterization of LTR and tax region.

We report the molecular and epidemiological characterization of 128 human T cell lymphotropic virus type 1 (HTLV-1) isolates from Brazilian patients with different clinical manifestations of the infection. Thirty-two percent of the patients were asymptomatic, 44% had HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 23% had adult T cell leukemia/lymphoma (ATLL). Phylogenetic analysis performed using part of the LTR region of the viral genome revealed that all Brazilian isolates belonged to the Cosmopolitan subtype, with the following distribution within the Transcontinental subgroup: 81.6% within the Latin American cluster and 15.8% outside the Latin American cluster. Two isolates belonged to the Japanese subgroup. Molecular analysis of the tax region showed a high nucleotide similarity ( approximately 99%) with 41 prototype sequences, including the ATK-1 isolate. The mean number of nucleotide substitutions ranged from 1 to 8. Five specific nucleotide substitutions, C7401T, T7914C, C7920T, C7982T, and G8231A, were highly conserved among the Brazilian isolates (79.6%), with a frequency ranging from 81.6% to 100% in the sample group and from 18.4% to 24.1% in the prototypes used, suggesting the existence of a molecular signature. These changes were not correlated with a specific clinical status of the patients and could be a molecular characteristic of the HTLV-1 strains that circulate in Brazil.

Adolescent↗

PubMed2003

Isolation of methicillin-resistant coagulase-negative staphylococci from patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and comparison of different molecular techniques for discriminating isolates of Staphylococcus epidermidis.

Coagulase-negative staphylococci (CNS) have emerged as an important pathogen in nosocomial infections. About 80%-90% of CNS isolates associated with hospital infections are methicillin-resistant coagulase-negative staphylococci (MRCNS). The aims of this study were to screen for MRCNS isolates in the flora of a small population of patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and to evaluate the discriminatory power of different molecular methods: pulsed-field gel electrophoresis (PFGE), mecA location, ClaI/mecA polymorphism and arbitrarily primed polymerase chain reaction (AP-PCR) for characterizing isolates of methicillin-resistant Staphylococcus epidermidis (MRSE). Seventy-nine CNS isolates were recovered from the 11 CAPD patients studied. Using a methicillin screening agar and a DNA specific mecA probe we verified that 30 of the 79 (38%) CNS isolates were resistant to methicillin (MRCNS). Twenty-two of the 30 MRCNS (73%) were MRSE, 7 (23%) methicillin-resistant S. haemolyticus (MRSH(ae)) and 1 (3%) methicillin-resistant S. hominis (MRSH(om)). All patients analyzed carried MRCNS in their flora, in one or more sites. Since CAPD patients have high risk for developing peritonitis, the colonization of these patients with MRCNS might represent an additional problem, due to the therapeutic restrictions imposed by these multiresistant isolates. A wide genetic diversity was verified when the PFGE of the MRSE isolates was analyzed. The 22 MRSE isolates displayed a total of 15 PFGE different patterns (11 PFGE types and 4 subtypes). The location of mecA in the SmaI-fragmented genome DNA did not bring any additional advantage for epidemiologic characterization of the isolates. The ClaI/mecA polymorphism was able to correctly discriminate 12 from the 15 PFGE patterns. In addition, the DNA of 20 MRSE isolates were used for AP-PCR typing. These isolates belonged to 14 PFGE patterns (11 types and 3 subtypes) and displayed 15 genotypes (for the association of PFGE, mecA location and ClaI/mecA polymorphism). A total of 17 different amplification patterns was verified using the primer 1. Only for 2 genotypes, strains having identical genetic backgrounds were further discriminated by AP-PCR (2 of 15 genotypes (87%) for AP-PCR and 1 of 15 genotypes for PFGE; (93%). Concluding, our results indicated that the AP-PCR can be an alternative and useful tool for monitoring and genotyping MRSE colonization and also to molecular characterizing MRSE outbreaks in hospitals.

Anti-Bacterial Agents↗

PubMed1998

Infection of baboons with a simian immunodeficiency virus/HIV-1 chimeric virus constructed with an HIV-1 Thai subtype E envelope.

OBJECTIVE: To construct an infectious chimeric simian immunodeficiency virus/HIV-1 (SHIV) with the envelope of a Thai subtype E HIV-1 strain for use in a non-human primate model. METHODS: A novel SHIV genome was derived using the sequences of the ectodomain of the envelope gene from the Thai subtype E strain, HIV-1(9466). This SHIV (SHIV9466.33) was recovered by cocultivation from human peripheral blood mononuclear cells (PBMC) after transfection of human rhabdosarcoma cells. Rhesus macaque and baboon PBMC were screened in vitro for susceptibility to infection with SHIV9466.33. After successful infection of baboon PBMC, four animals were inoculated intravenously with SHIV9466.33 and monitored for plasma viral RNA, virus isolation from the PBMC, seroconversion, T-cell subsets, and signs of disease. RESULTS: SHIV9466.33 was able to infect PBMC from 12 out of 14 baboons. All four of the baboons selected for in vivo inoculation became infected. Peak plasma viral RNA levels of 8000 to 700,000 RNA copies/ml were measured at 2 weeks post-inoculation. Virus was isolated from the PBMC of all four baboons during acute infection, and all seroconverted. Although transient declines in CD4+ T-cells were observed during early infection, CD4+ levels remained within normal ranges thereafter. In contrast, in vitro cultures of PBMC of four rhesus macaques were not susceptible to infection with SHIV9466.33. CONCLUSION: SHIV9466.33 containing an HIV-1 subtype E envelope displayed tropism for baboon PBMC but not for rhesus macaque PBMC. This chimeric virus established infection and induced antiviral antibodies in baboons inoculated by the intravenous route with cell-free virus. Thus, infection of baboons with SHIV9466.33 will serve as an important animal model for future studies of HIV-1 vaccine efficacy.

Animals↗

PubMed2006

Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorder.

We conducted a 9-cM genome scan in a large bipolar pedigree sample from the National Institute of Mental Health genetics initiative (1060 individuals from 154 multiplex families). We performed parametric and nonparametric analyses using both standard diagnostic models and comorbid conditions thought to identify phenotypic subtypes: psychosis, suicidal behavior, and panic disorder. Our strongest linkage signals (genome-wide significance) were observed on chromosomes 10q25, 10p12, 16q24, 16p13, and 16p12 using standard diagnostic models, and on 6q25 (suicidal behavior), 7q21 (panic disorder) and 16p12 (psychosis) using phenotypic subtypes. Several other regions were suggestive of linkage, including 1p13 (psychosis), 1p21 (psychosis), 1q44, 2q24 (suicidal behavior), 2p25 (psychosis), 4p16 (psychosis, suicidal behavior), 5p15, 6p25 (psychosis), 8p22 (psychosis), 8q24, 10q21, 10q25 (suicidal behavior), 10p11 (psychosis), 13q32 and 19p13 (psychosis). Over half the implicated regions were identified using phenotypic subtypes. Several regions - 1p, 1q, 6q, 8p, 13q and 16p - have been previously reported to be linked to bipolar disorder. Our results suggest that dissection of the disease phenotype can enrich the harvest of linkage signals and expedite the search for susceptibility genes. This is the first large-scale linkage scan of bipolar disorder to analyze simultaneously bipolar disorder, psychosis, suicidal behavior, and panic disorder.

Bipolar Disorder↗