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1.
J Gen Virol ; 95(Pt 2): 350-362, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24243730

RESUMO

Type I alveolar epithelial cells are a replicative niche for influenza in vivo, yet their response to infection is not fully understood. To better characterize their cellular responses, we have created an immortalized murine lung epithelial type I cell line (LET1). These cells support spreading influenza virus infection in the absence of exogenous protease and thus permit simultaneous analysis of viral replication dynamics and host cell responses. LET1 cells can be productively infected with human, swine and mouse-adapted strains of influenza virus and exhibit expression of an antiviral transcriptional programme and robust cytokine secretion. We characterized influenza virus replication dynamics and host responses of lung type I epithelial cells and identified the capacity of epithelial cell-derived type I IFN to regulate specific modules of antiviral effectors to establish an effective antiviral state. Together, our results indicate that the type I epithelial cell can play a major role in restricting influenza virus infection without contribution from the haematopoietic compartment.


Assuntos
Células Epiteliais/imunologia , Células Epiteliais/virologia , Imunidade Inata , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Replicação Viral , Animais , Linhagem Celular , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
2.
Blood Cancer Discov ; 4(5): 365-373, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37486974

RESUMO

The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus

Assuntos
Mieloma Múltiplo , Neoplasias de Plasmócitos , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/uso terapêutico , Prognóstico , Mieloma Múltiplo/terapia , Imunoterapia Adotiva , Neoplasia Residual
3.
J Virol ; 82(22): 11140-51, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18799582

RESUMO

TRIM5alpha has been shown to be a major postentry determinant of the host range for gammaretroviruses and lentiviruses and, more recently, spumaviruses. However, the restrictive potential of TRIM5alpha against other retroviruses has been largely unexplored. We sought to determine whether or not Mason-Pfizer monkey virus (M-PMV), a prototype betaretrovirus isolated from rhesus macaques, was sensitive to restriction by TRIM5alpha. Cell lines from both Old World and New World primate species were screened for their susceptibility to infection by vesicular stomatitis virus G protein pseudotyped M-PMV. All of the cell lines tested that were established from Old World primates were found to be susceptible to M-PMV infection. However, fibroblasts established from three New World monkey species specifically resisted infection by this virus. Exogenously expressing TRIM5alpha from either tamarin or squirrel monkeys in permissive cell lines resulted in a block to M-PMV infection. Restriction in the resistant cell line of spider monkey origin was determined to occur at a postentry stage. However, spider monkey TRIM5alpha expression in permissive cells failed to restrict M-PMV infection, and interference with endogenous TRIM5alpha in the spider monkey fibroblasts failed to relieve the block to infectivity. Our results demonstrate that TRIM5alpha specificity extends to betaretroviruses and suggest that New World monkeys have evolved additional mechanisms to restrict the infection of at least one primate betaretrovirus.


Assuntos
Vírus dos Macacos de Mason-Pfizer/crescimento & desenvolvimento , Vírus dos Macacos de Mason-Pfizer/imunologia , Proteínas/imunologia , Internalização do Vírus , Animais , Fatores de Restrição Antivirais , Proteínas de Transporte/imunologia , Linhagem Celular , Cercopithecidae , Humanos , Vírus dos Macacos de Mason-Pfizer/fisiologia , Platirrinos , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Replicação Viral
4.
Chem Biol ; 11(10): 1413-22, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15489168

RESUMO

Factor VIII is a critical member of the blood coagulation cascade. It binds to the membrane surfaces of activated platelets at the site of vascular injury via a highly specific interaction between factor VIII's carboxy-terminal C2 domain and their phosphatidylserine-rich lipid bilayer. We have identified small-molecule inhibitors of factor VIII's membrane binding activity that have IC50 values as low as 2.5 microM. This interaction is approximately 10(3)-fold tighter than that of free o-phospho-L-serine. These compounds also inhibit factor VIII-dependent activation of factor X, indicating that disruption of membrane lipid binding leads to inhibition of the intrinsic coagulation pathway. The tightest binding inhibitor is specific and does not prevent membrane binding by the closely related coagulation factor V. These results indicate that this and related compounds may be used as leads to develop novel antithrombotic agents.


Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/isolamento & purificação , Inibidores dos Fatores de Coagulação Sanguínea/metabolismo , Fator VIII/antagonistas & inibidores , Fator VIII/química , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/química , Inibidores dos Fatores de Coagulação Sanguínea/química , Relação Dose-Resposta a Droga , Fator VIII/metabolismo , Concentração Inibidora 50 , Proteínas de Membrana/metabolismo , Peso Molecular , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
5.
Sci Data ; 1: 140033, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25977790

RESUMO

The Systems Biology for Infectious Diseases Research program was established by the U.S. National Institute of Allergy and Infectious Diseases to investigate host-pathogen interactions at a systems level. This program generated 47 transcriptomic and proteomic datasets from 30 studies that investigate in vivo and in vitro host responses to viral infections. Human pathogens in the Orthomyxoviridae and Coronaviridae families, especially pandemic H1N1 and avian H5N1 influenza A viruses and severe acute respiratory syndrome coronavirus (SARS-CoV), were investigated. Study validation was demonstrated via experimental quality control measures and meta-analysis of independent experiments performed under similar conditions. Primary assay results are archived at the GEO and PeptideAtlas public repositories, while processed statistical results together with standardized metadata are publically available at the Influenza Research Database (www.fludb.org) and the Virus Pathogen Resource (www.viprbrc.org). By comparing data from mutant versus wild-type virus and host strains, RNA versus protein differential expression, and infection with genetically similar strains, these data can be used to further investigate genetic and physiological determinants of host responses to viral infection.


Assuntos
Interações Hospedeiro-Patógeno , Vírus da Influenza A , Influenza Humana/virologia , Infecções por Orthomyxoviridae/virologia , Animais , Coleta de Dados , Bases de Dados Factuais , Humanos , Vírus da Influenza A/patogenicidade , Vírus da Influenza A/fisiologia , Influenza Humana/fisiopatologia , Camundongos , Infecções por Orthomyxoviridae/fisiopatologia , Biologia de Sistemas
6.
Science ; 316(5832): 1756-8, 2007 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-17588933

RESUMO

Primate genomes contain a large number of endogenous retroviruses and encode evolutionarily dynamic proteins that provide intrinsic immunity to retroviral infections. We report here the resurrection of the core protein of a 4-million-year-old endogenous virus from the chimpanzee genome and show that the human variant of the intrinsic immune protein TRIM5alpha can actively prevent infection by this virus. However, we suggest that selective changes that have occurred in the human lineage during the acquisition of resistance to this virus, and perhaps similar viruses, may have left our species more susceptible to infection by human immunodeficiency virus type 1 (HIV-1).


Assuntos
Proteínas de Transporte/fisiologia , Retrovirus Endógenos/fisiologia , Animais , Fatores de Restrição Antivirais , Sequência de Bases , Evolução Biológica , Proteínas de Transporte/genética , Gatos , Linhagem Celular , DNA , Suscetibilidade a Doenças , Retrovirus Endógenos/genética , Evolução Molecular , Gorilla gorilla , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1 , Humanos , Imunidade Inata/genética , Macaca mulatta , Dados de Sequência Molecular , Pan troglodytes/genética , Pan troglodytes/virologia , Infecções por Retroviridae/genética , Infecções por Retroviridae/imunologia , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
7.
J Virol ; 80(2): 875-82, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16378989

RESUMO

It is well established that many host factors are involved in the replication of human immunodeficiency virus (HIV) type 1. One host protein, uracil DNA glycosylase 2 (UNG2), binds to multiple viral proteins and is packaged into HIV type 1 virions. UNG initiates the removal of uracils from DNA, and this has been proposed to be important both for reverse transcription and as a mediator to the antiviral effect of virion-incorporated Apobec3G, a cytidine deaminase that generates numerous uracils in the viral DNA during virus replication. We used a natural human UNG-/- cell line as well as cells that express a potent catalytic active-site inhibitor of UNG to assess the effects of removing UNG activity on HIV infectivity. In both cases, we find UNG2 activity and protein to be completely dispensable for virus replication. Moreover, we find that virion-associated UNG2 does not affect the loss of infectivity caused by Apobec3G.


Assuntos
DNA Glicosilases/fisiologia , Infecções por HIV/virologia , HIV-1/fisiologia , Nucleosídeo Desaminases/fisiologia , Proteínas Repressoras/fisiologia , Desaminase APOBEC-3G , Linhagem Celular , Citidina Desaminase , Humanos , Replicação Viral
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