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Pesquisa : B04.613.807.375 [Categoria DeCS]
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  1 / 1102 MEDLINE  
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[PMID]:28895843
[Au] Autor:Kohn DB
[Ad] Endereço:Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: dkohn1@mednet.ucla.edu.
[Ti] Título:Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy.
[So] Source:Hematol Oncol Clin North Am;31(5):721-735, 2017 Oct.
[Is] ISSN:1558-1977
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gene therapy using hematopoietic stem cells (HSC) has developed over the past 3 decades, with progressive improvements in the efficacy and safety. Autologous transplantation of HSC modified with murine gammaretroviral vectors first showed clinical benefits for patients with several primary immune deficiencies, but some of these patients suffered complications from vector-related genotoxicity. Lentiviral vectors have been used recently for gene addition to HSC and have yielded clinical benefits for primary immune deficiencies, metabolic diseases, and hemoglobinopathies, without vector-related complications. Gene editing using site-specific endonucleases is emerging as a promising technology for gene therapy and is moving into clinical trials.
[Mh] Termos MeSH primário: Terapia Genética
Células-Tronco Hematopoéticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Ensaios Clínicos como Assunto
Gammaretrovirus/genética
Edição de Genes
Terapia Genética/efeitos adversos
Terapia Genética/história
Terapia Genética/métodos
Terapia Genética/tendências
Vetores Genéticos
Células-Tronco Hematopoéticas/citologia
História do Século XX
História do Século XXI
Recombinação Homóloga
Seres Humanos
Lentivirus/genética
[Pt] Tipo de publicação:HISTORICAL ARTICLE; JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE


  2 / 1102 MEDLINE  
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[PMID]:28895844
[Au] Autor:Biasco L; Rothe M; Schott JW; Schambach A
[Ad] Endereço:Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA; University College London, UCL Great Ormond Street Institute of Child Health, UCL Faculty of Population Health Sciences, 30 Guilford Street, London
[Ti] Título:Integrating Vectors for Gene Therapy and Clonal Tracking of Engineered Hematopoiesis.
[So] Source:Hematol Oncol Clin North Am;31(5):737-752, 2017 Oct.
[Is] ISSN:1558-1977
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gene therapy using autologous or allogeneic cells offers promising possibilities to treat inherited and acquired diseases, ideally leading to a long-lasting therapeutic correction. This article summarizes efforts that use integrating vectors derived from retroviruses and transposons, and briefly explains integrating vector biology and integration site analysis and recent successful application of this technology in clinical trials. Moreover, outlined is how these vectors can be used for cancer gene discovery and clonal tracking of benign and malignant hematopoiesis to gain insights into the dynamics of hematopoiesis.
[Mh] Termos MeSH primário: Rastreamento de Células
Evolução Clonal
Engenharia Genética
Terapia Genética
Vetores Genéticos
Hematopoese
Células-Tronco Hematopoéticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Ensaios Clínicos como Assunto
Elementos de DNA Transponíveis
Gammaretrovirus/genética
Terapia Genética/efeitos adversos
Terapia Genética/métodos
Células-Tronco Hematopoéticas/citologia
Seres Humanos
Lentivirus/genética
Mutagênese Insercional
Transgenes
Integração Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (DNA Transposable Elements)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE


  3 / 1102 MEDLINE  
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[PMID]:28768854
[Au] Autor:Kawasaki J; Kawamura M; Ohsato Y; Ito J; Nishigaki K
[Ad] Endereço:Laboratory of Molecular Immunology and Infectious Disease, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan.
[Ti] Título:Presence of a Shared 5'-Leader Sequence in Ancestral Human and Mammalian Retroviruses and Its Transduction into Feline Leukemia Virus.
[So] Source:J Virol;91(20), 2017 Oct 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recombination events induce significant genetic changes, and this process can result in virus genetic diversity or in the generation of novel pathogenicity. We discovered a new recombinant feline leukemia virus (FeLV) gene harboring an unrelated insertion, termed the X region, which was derived from endogenous gammaretrovirus 4 (FcERV-gamma4). The identified FcERV-gamma4 proviruses have lost their coding capabilities, but some can express their viral RNA in feline tissues. Although the X-region-carrying recombinant FeLVs appeared to be replication-defective viruses, they were detected in 6.4% of tested FeLV-infected cats. All isolated recombinant FeLV clones commonly incorporated a middle part of the FcERV-gamma4 5'-leader region as an X region. Surprisingly, a sequence corresponding to the portion contained in all X regions is also present in at least 13 endogenous retroviruses (ERVs) observed in the cat, human, primate, and pig genomes. We termed this shared genetic feature the commonly shared (CS) sequence. Despite our phylogenetic analysis indicating that all CS-sequence-carrying ERVs are classified as gammaretroviruses, no obvious closeness was revealed among these ERVs. However, the Shannon entropy in the CS sequence was lower than that in other parts of the provirus genome. Notably, the CS sequence of human endogenous retrovirus T had 73.8% similarity with that of FcERV-gamma4, and specific signals were detected in the human genome by Southern blot analysis using a probe for the FcERV-gamma4 CS sequence. Our results provide an interesting evolutionary history for CS-sequence circulation among several distinct ancestral viruses and a novel recombined virus over a prolonged period. Recombination among ERVs or modern viral genomes causes a rapid evolution of retroviruses, and this phenomenon can result in the serious situation of viral disease reemergence. We identified a novel recombinant FeLV gene that contains an unrelated sequence, termed the X region. This region originated from the 5' leader of FcERV-gamma4, a replication-incompetent feline ERV. Surprisingly, a sequence corresponding to the X region is also present in the 5' portion of other ERVs, including human endogenous retroviruses. Scattered copies of the ERVs carrying the unique genetic feature, here named the commonly shared (CS) sequence, were found in each host genome, suggesting that ancestral viruses may have captured and maintained the CS sequence. More recently, a novel recombinant FeLV hijacked the CS sequence from inactivated FcERV-gamma4 as the X region. Therefore, tracing the CS sequences can provide unique models for not only the modern reservoir of new recombinant viruses but also the genetic features shared among ancient retroviruses.
[Mh] Termos MeSH primário: Regiões 5´ não Traduzidas/genética
Retrovirus Endógenos/genética
Genes gag
Genoma Viral
Vírus da Leucemia Felina/genética
Recombinação Genética
[Mh] Termos MeSH secundário: Animais
Gatos/virologia
Evolução Molecular
Gammaretrovirus/genética
Seres Humanos/virologia
Leucemia Felina/virologia
Mamíferos/genética
Mamíferos/virologia
Filogenia
Provírus/genética
Provírus/fisiologia
RNA Viral/genética
Suínos/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5' Untranslated Regions); 0 (RNA, Viral)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE


  4 / 1102 MEDLINE  
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[PMID]:28437635
[Au] Autor:Colon-Moran W; Argaw T; Wilson CA
[Ad] Endereço:Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
[Ti] Título:Three cysteine residues of SLC52A1, a receptor for the porcine endogenous retrovirus-A (PERV-A), play a critical role in cell surface expression and infectivity.
[So] Source:Virology;507:140-150, 2017 Jul.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Porcine endogenous retrovirus-A (PERV-A), a gammaretrovirus, infects human cells in vitro, thus raising the potential risk of cross-species transmission in xenotransplantation. Two members of the solute carrier family 52 (SLC52A1 and SLC52A2) are PERV-A receptors. Site-directed mutagenesis of the cDNA encoding SLC52A1 identified that only one of two putative glycosylation signals is occupied by glycans. In addition, we showed that glycosylation of SLC52A1 is not necessary for PERV-A receptor function. We also identified that at a minimum, three cysteine residues are sufficient for SLC52A1 cell surface expression. Mutation of cysteine at position 365 and either of the two cysteine residues in the C-terminal tail at positions 442 or 446 reduced SLC52A1 surface expression and PERV-A infection suggesting that these residues may contribute to overall structural stability and receptor function. Understanding interactions between PERV-A and its cellular receptor may provide novel strategies to prevent zoonotic infection in the setting of xenotransplantation.
[Mh] Termos MeSH primário: Cisteína/metabolismo
Retrovirus Endógenos/patogenicidade
Gammaretrovirus/metabolismo
Receptores Acoplados a Proteínas-G/química
Receptores Virais/química
Receptores Virais/metabolismo
Infecções por Retroviridae/veterinária
Doenças dos Suínos/metabolismo
[Mh] Termos MeSH secundário: Animais
Cisteína/química
Cisteína/genética
Retrovirus Endógenos/genética
Retrovirus Endógenos/fisiologia
Gammaretrovirus/classificação
Gammaretrovirus/genética
Glicosilação
Receptores Acoplados a Proteínas-G/genética
Receptores Acoplados a Proteínas-G/metabolismo
Receptores Virais/genética
Infecções por Retroviridae/genética
Infecções por Retroviridae/metabolismo
Infecções por Retroviridae/virologia
Suínos
Doenças dos Suínos/genética
Doenças dos Suínos/virologia
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (Receptors, Virus); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170425
[St] Status:MEDLINE


  5 / 1102 MEDLINE  
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[PMID]:28351939
[Au] Autor:Cooper AR; Lill GR; Shaw K; Carbonaro-Sarracino DA; Davila A; Sokolic R; Candotti F; Pellegrini M; Kohn DB
[Ad] Endereço:Department of Microbiology, Immunology and Molecular Genetics and.
[Ti] Título:Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients.
[So] Source:Blood;129(19):2624-2635, 2017 May 11.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Retroviral gene therapy has proved efficacious for multiple genetic diseases of the hematopoietic system, but roughly half of clinical gene therapy trial protocols using gammaretroviral vectors have reported leukemias in some of the patients treated. In dramatic contrast, 39 adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) patients have been treated with 4 distinct gammaretroviral vectors without oncogenic consequence. We investigated clonal dynamics and diversity in a cohort of 15 ADA-SCID children treated with gammaretroviral vectors and found clear evidence of genotoxicity, indicated by numerous common integration sites near proto-oncogenes and by increased abundance of clones with integrations near and These clones showed stable behavior over multiple years and never expanded to the point of dominance or dysplasia. One patient developed a benign clonal dominance that could not be attributed to insertional mutagenesis and instead likely resulted from expansion of a transduced natural killer clone in response to chronic Epstein-Barr virus viremia. Clonal diversity and T-cell repertoire, measured by vector integration site sequencing and T-cell receptor ß-chain rearrangement sequencing, correlated significantly with the amount of busulfan preconditioning delivered to patients and to CD34 cell dose. These data, in combination with results of other ADA-SCID gene therapy trials, suggest that disease background may be a crucial factor in leukemogenic potential of retroviral gene therapy and underscore the importance of cytoreductive conditioning in this type of gene therapy approach.
[Mh] Termos MeSH primário: Adenosina Desaminase/deficiência
Agamaglobulinemia/genética
Agamaglobulinemia/terapia
Antineoplásicos Alquilantes/uso terapêutico
Bussulfano/uso terapêutico
Gammaretrovirus/genética
Terapia Genética/métodos
Vetores Genéticos/uso terapêutico
Imunodeficiência Combinada Severa/genética
Imunodeficiência Combinada Severa/terapia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Adenosina Desaminase/genética
Agamaglobulinemia/patologia
Criança
Proteínas de Ligação a DNA/genética
Vetores Genéticos/genética
Seres Humanos
Proteínas com Domínio LIM/genética
Proteína do Locus do Complexo MDS1 e EVI1
Proteínas Proto-Oncogênicas/genética
Proto-Oncogenes/genética
Imunodeficiência Combinada Severa/patologia
Linfócitos T/citologia
Linfócitos T/efeitos dos fármacos
Linfócitos T/metabolismo
Linfócitos T/patologia
Fatores de Transcrição/genética
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents, Alkylating); 0 (DNA-Binding Proteins); 0 (LIM Domain Proteins); 0 (LMO2 protein, human); 0 (MDS1 and EVI1 Complex Locus Protein); 0 (MECOM protein, human); 0 (Proto-Oncogene Proteins); 0 (Transcription Factors); EC 3.5.4.4 (Adenosine Deaminase); G1LN9045DK (Busulfan)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170330
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-12-756734


  6 / 1102 MEDLINE  
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[PMID]:27881645
[Au] Autor:Chappell KJ; Brealey JC; Amarilla AA; Watterson D; Hulse L; Palmieri C; Johnston SD; Holmes EC; Meers J; Young PR
[Ad] Endereço:School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Queensland, Australia k.chappell@uq.edu.au p.young@uq.edu.au.
[Ti] Título:Phylogenetic Diversity of Koala Retrovirus within a Wild Koala Population.
[So] Source:J Virol;91(3), 2017 Feb 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Koala populations are in serious decline across many areas of mainland Australia, with infectious disease a contributing factor. Koala retrovirus (KoRV) is a gammaretrovirus present in most wild koala populations and captive colonies. Five subtypes of KoRV (A to E) have been identified based on amino acid sequence divergence in a hypervariable region of the receptor binding domain of the envelope protein. However, analysis of viral genetic diversity has been conducted primarily on KoRV in captive koalas housed in zoos in Japan, the United States, and Germany. Wild koalas within Australia have not been comparably assessed. Here we report a detailed analysis of KoRV genetic diversity in samples collected from 18 wild koalas from southeast Queensland. By employing deep sequencing we identified 108 novel KoRV envelope sequences and determined their phylogenetic diversity. Genetic diversity in KoRV was abundant and fell into three major groups; two comprised the previously identified subtypes A and B, while the third contained the remaining hypervariable region subtypes (C, D, and E) as well as four hypervariable region subtypes that we newly define here (F, G, H, and I). In addition to the ubiquitous presence of KoRV-A, which may represent an exclusively endogenous variant, subtypes B, D, and F were found to be at high prevalence, while subtypes G, H, and I were present in a smaller number of animals. IMPORTANCE: Koala retrovirus (KoRV) is thought to be a significant contributor to koala disease and population decline across mainland Australia. This study is the first to determine KoRV subtype prevalence among a wild koala population, and it significantly expands the total number of KoRV sequences available, providing a more precise picture of genetic diversity. This understanding of KoRV subtype prevalence and genetic diversity will be important for conservation efforts attempting to limit the spread of KoRV. Furthermore, KoRV is one of the only retroviruses shown to exist in both endogenous (transmitted vertically to offspring in the germ line DNA) and exogenous (horizontally transmitted between infected individuals) forms, a division of fundamental evolutionary importance.
[Mh] Termos MeSH primário: Gammaretrovirus/classificação
Gammaretrovirus/genética
Variação Genética
Phascolarctidae/virologia
Filogenia
Infecções por Retroviridae/veterinária
[Mh] Termos MeSH secundário: Animais
Animais Selvagens
Evolução Molecular
Feminino
Produtos do Gene env
Masculino
Motivos de Nucleotídeos
Filogeografia
Recombinação Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gene Products, env)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161125
[St] Status:MEDLINE


  7 / 1102 MEDLINE  
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[PMID]:28484175
[Au] Autor:Miyazawa T; Shimode S; Nakagawa S
[Ad] Endereço:Institute for Virus Research, Kyoto University, Kyoto, Japan.
[Ti] Título:RD-114 virus story: from RNA rumor virus to a useful viral tool for elucidating the world cats' journey.
[So] Source:Uirusu;66(1):21-30, 2016.
[Is] ISSN:0042-6857
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:RD-114 virus is a feline endogenous retrovirus (ERV) isolated from human rhabdomyosarcoma in 1971 and classified as endogenous gammaretrovirus in domestic cats (Felis catus). Based on the previous reports in 70's, it has been considered that a horizontal, infectious event occurred to transfer the virus from ancient baboon species to ancient cat species, whereupon it became endogenous in the cat species about several million years ago in Mediterranean Basin. Although it has been believed that all domestic cats harbor infectious RD-114 provirus in their genome, we revealed that cats do not have infectious RD-114 viral loci, but infectious RD-114 virus is resurrected by recombination between uninfectious RD-114 virus-related ERVs [here we designated them as RD-114-related sequences (RDRSs)]. Further, we also revealed the RDRSs which would potentially be resurrected as RD-114 virus (here we refer to them as ''new'' RDRSs) had entered the genome of the domestic cat after domestication of the cat around 10 thousand years ago. The fractions and positions of RDRSs in the cat genome differed in Western and Eastern cat populations and cat breeds. Our study revealed that RDRS would be a useful tool for elucidating the world travel routes of domestic cats after domestication.
[Mh] Termos MeSH primário: Gatos/genética
Gatos/virologia
Gammaretrovirus
[Mh] Termos MeSH secundário: Animais
Domesticação
Gammaretrovirus/genética
Gammaretrovirus/patogenicidade
Genoma
Seres Humanos
Filogenia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171015
[Lr] Data última revisão:
171015
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.2222/jsv.66.21


  8 / 1102 MEDLINE  
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[PMID]:27999419
[Au] Autor:Denner J
[Ad] Endereço:Robert Koch Institute, 13353 Berlin, Germany. DennerJ@rki.de.
[Ti] Título:Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV) and the Koala Retrovirus (KoRV).
[So] Source:Viruses;8(12), 2016 Dec 20.
[Is] ISSN:1999-4915
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Transspecies transmission of retroviruses is a frequent event, and the human immunodeficiency virus-1 (HIV-1) is a well-known example. The gibbon ape leukaemia virus (GaLV) and koala retrovirus (KoRV), two gammaretroviruses, are also the result of a transspecies transmission, however from a still unknown host. Related retroviruses have been found in Southeast Asian mice although the sequence similarity was limited. Viruses with a higher sequence homology were isolated from , the Australian and Indonesian grassland melomys. However, only the habitats of the koalas and the grassland melomys in Australia are overlapping, indicating that the melomys virus may not be the precursor of the GaLV. Viruses closely related to GaLV/KoRV were also detected in bats. Therefore, given the fact that the habitats of the gibbons in Thailand and the koalas in Australia are far away, and that bats are able to fly over long distances, the hypothesis that retroviruses of bats are the origin of GaLV and KoRV deserves consideration. Analysis of previous transspecies transmissions of retroviruses may help to evaluate the potential of transmission of related retroviruses in the future, e.g., that of porcine endogenous retroviruses (PERVs) during xenotransplantation using pig cells, tissues or organs.
[Mh] Termos MeSH primário: Transmissão de Doença Infecciosa
Evolução Molecular
Gammaretrovirus/classificação
Gammaretrovirus/genética
Infecções por Retroviridae/veterinária
[Mh] Termos MeSH secundário: Animais
Austrália
Quirópteros
Gammaretrovirus/isolamento & purificação
Hylobates
Camundongos
Phascolarctidae
Infecções por Retroviridae/virologia
Tailândia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE


  9 / 1102 MEDLINE  
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[PMID]:27423269
[Au] Autor:Liu Q; Yan Y; Kozak CA
[Ad] Endereço:Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
[Ti] Título:Permissive XPR1 gammaretrovirus receptors in four mammalian species are functionally distinct in interference tests.
[So] Source:Virology;497:53-58, 2016 Oct.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Xenotropic/polytropic mouse leukemia viruses (X/P-MLVs) use the XPR1 gammaretrovirus receptor for entry. X/P-MLV host range is defined by usage of naturally occurring restrictive XPR1 receptors, and is governed by polymorphisms in the virus envelope glycoprotein and in XPR1. Here, we examined receptors of four mammalian species permissive to all X/P-MLVs (Mus dunni, human, rabbit, mink). Interference assays showed the four to be functionally distinct. Preinfection with X-MLVs consistently blocked all nine XPR1-dependent viruses, while preinfection with P-MLVs and wild mouse X/P-MLVs produced distinctive interference patterns in the four cells. These patterns indicate shared usage of independent, but not always fully functional, receptor sites. XPR1 sequence comparisons identified candidate sites in receptor-determining regions that correlate with some interference patterns. The evolutionary record suggests that the X/P-MLV tropism variants evolved to adapt to host receptor polymorphisms, to circumvent blocks by competing viruses or to avoid host-encoded envelope glycoproteins acquired for defense.
[Mh] Termos MeSH primário: Gammaretrovirus/fisiologia
Receptores Acoplados a Proteínas-G/metabolismo
Receptores Virais/metabolismo
Infecções por Retroviridae/virologia
Interferência Viral
Tropismo Viral
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Evolução Biológica
Células Cultivadas
Seres Humanos
Camundongos
Vison
Polimorfismo Genético
Coelhos
Receptores Acoplados a Proteínas-G/química
Receptores Acoplados a Proteínas-G/genética
Receptores Virais/química
Receptores Virais/genética
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (Receptors, Virus); 0 (xenotropic and polytropic retrovirus receptor)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160718
[St] Status:MEDLINE


  10 / 1102 MEDLINE  
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[PMID]:26957223
[Au] Autor:Zhou S; Fatima S; Ma Z; Wang YD; Lu T; Janke LJ; Du Y; Sorrentino BP
[Ad] Endereço:Division of Experimental Hematology, Department of Hematology, Memphis, Tennessee, USA.
[Ti] Título:Evaluating the Safety of Retroviral Vectors Based on Insertional Oncogene Activation and Blocked Differentiation in Cultured Thymocytes.
[So] Source:Mol Ther;24(6):1090-1099, 2016 Jun.
[Is] ISSN:1525-0024
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Insertional oncogenesis due to retroviral (RV) vector integration has caused recurrent leukemia in multiple gene therapy trials, predominantly due to vector integration effects at the LMO2 locus. While currently available preclinical safety models have been used for evaluating vector safety, none have predicted or reproduced the recurrent LMO2 integrations seen in previous X-linked severe combined immunodeficiency (X-SCID) and Wiskott-Aldrich clinical gene therapy trials. We now describe a new assay for assessing vector safety that recapitulates naturally occurring insertions into Lmo2 and other T-cell proto-oncogenes leading to a preleukemic developmental arrest in primary murine thymocytes cultured in vitro. This assay was used to compare the relative oncogenic potential of a variety of gamma-RV and lentiviral vectors and to assess the risk conferred by various transcriptional elements contained in these genomes. Gamma-RV vectors that contained full viral long-terminal repeats were most prone to causing double negative 2 (DN2) arrest and led to repeated cases of Lmo2 pathway activation, while lentiviral vectors containing these same elements were significantly less prone to activate proto-oncogenes or cause DN2 arrest. This work provides a new preclinical assay that is especially relevant for assessing safety in SCID disorders and provides a new tool for designing safer RV vectors.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética
Gammaretrovirus/genética
Vetores Genéticos/efeitos adversos
Proteínas com Domínio LIM/genética
Lentivirus/genética
Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia
Timócitos/citologia
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/efeitos dos fármacos
Células Cultivadas
Modelos Animais de Doenças
Seres Humanos
Fatores de Transcrição MEF2/genética
Camundongos
Mutagênese Insercional
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
Timócitos/efeitos dos fármacos
Timócitos/transplante
Regulação para Cima
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (LIM Domain Proteins); 0 (Lmo2 protein, mouse); 0 (MEF2 Transcription Factors); 0 (Mef2c protein, mouse)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160310
[St] Status:MEDLINE



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