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1.
Viruses ; 14(10)2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36298708

RESUMO

Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus, causes adult T-cell leukemia-lymphoma, HTLV-1 associated myelopathy/tropical spastic paraparesis, and HTLV-1 uveitis. Currently, no antiretroviral therapies or vaccines are available for HTLV-1 infection. This study aimed to develop an antibody against the HTLV-1 envelope protein (Env) and apply it to a near-infrared photoimmuno-antimicrobial strategy (NIR-PIAS) to eliminate HTLV-1 infected cells. We established mouse monoclonal antibodies (mAbs) against HTLV-1 Env by immunization with a complex of liposome and the recombinant protein. Detailed epitope mapping revealed that one of the mAbs bound to the proline-rich region of gp46 and exhibited no obvious neutralizing activity to inhibit viral infection. Instead, the mAb was rarely internalized intracellularly and remained on the cell surface of HTLV-1-infected cells. The antibody conjugated to the photosensitive dye IRDye700Dx recognized HTLV-1 infected cells and killed them following NIR irradiation. These results suggest that the novel mAb and NIR-PIAS could be developed as a new targeted therapeutic tool against HTLV-1 infected cells.


Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Camundongos , Animais , Humanos , Proteínas Oncogênicas de Retroviridae , Anticorpos Monoclonais , Lipossomos , Produtos do Gene env , Proteínas Recombinantes , Glicoproteínas , Prolina
2.
Biochim Biophys Acta Proteins Proteom ; 1869(11): 140708, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34343702

RESUMO

Human T-cell leukemia virus type 1 (HTLV-1) infection of host cells is mainly mediated by interactions with the viral envelope glycoprotein surface unit (SU) and three host receptors: heparan sulfate proteoglycan, neuropilin-1 (Nrp1), and glucose transporter type 1. Residues 90-94 of SU are considered as a Nrp1 binding site, and our previous results show that an SU peptide consisting of residues 85-94 can bind directly to the Nrp1 b1 domain with a binding affinity of 7.4 µM. Therefore, the SU peptide is expected to be a good model to investigate the SU-Nrp1 interaction. Recently, the N93D mutation in the Nrp1 b1 binding region of the SU was identified in symptomatic patients with HTLV-1 infections in the Brazilian Amazon. However, it remains unclear how the SU-N93D mutation affects Nrp1 b1 binding. To elucidate the impact of the substituted Asp93 of SU on Nrp1 b1 binding, we analyzed the interaction between the SU-N93D peptide and Nrp1 b1 using isothermal titration calorimetry and nuclear magnetic resonance. The SU-N93D peptide binds directly to Nrp1 b1 with a binding affinity of 3.5 µM, which is approximately two-fold stronger than wild-type. This stronger binding is likely a result of the interaction between the substituted residue Asp93 of the N93D peptide and the four residues Trp301, Lys347, Glu348, and Thr349 of Nrp1 b1. Our results suggest that the interaction of SU Asp93 with the four residues of Nrp1 b1 renders the high affinity of the N93D mutant for Nrp1 b1 binding during HTLV-1 entry.


Assuntos
Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Mutação de Sentido Incorreto , Neuropilina-1/metabolismo , Proteínas do Envelope Viral/metabolismo , Sítios de Ligação , Produtos do Gene env , Infecções por HTLV-I/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Neuropilina-1/química , Ligação Proteica , Proteínas Oncogênicas de Retroviridae , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética
3.
J Virol ; 94(21)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796072

RESUMO

Guanylate binding protein 5 (GBP5) belongs to the GTPase subfamily, which is mainly induced by interferon gamma (IFN-γ) and is involved in many important cellular processes, including inflammasome activation and innate immunity against a wide variety of microbial pathogens. However, it is unknown whether GBP5 inhibits respiratory syncytial virus (RSV) infection. In this study, we identified GBP5 as an effector of the anti-RSV activity of IFN-γ and found that in children, the weaker immune response, especially the weaker IFN-γ response and the decreased GBP5 expression, leads to RSV susceptibility. Furthermore, we revealed that GBP5 reduced the cell-associated levels of the RSV small hydrophobic (SH) protein, which was identified as a viroporin. In contrast, overexpression of the SH protein rescued RSV replication in the presence of GBP5. The GBP5-induced decrease in intracellular SH protein levels is because GBP5 promotes the release of the SH protein into the cell culture. Moreover, the GBP5 C583A mutants with changes at the C terminus or the GBP5 ΔC mutant lacking the C-terminal region, which impairs GBP5 localization in the Golgi, could not inhibit RSV infection, whereas the GTPase-defective GBP5 maintained RSV inhibition, suggesting that Golgi localization but not the GTPase activity of GBP5 is required for RSV inhibition. Interestingly, we found that RSV infection or RSV G protein downregulates GBP5 expression by upregulating DZIP3, an E3 ligase, which induces GBP5 degradation through the K48 ubiquitination and proteasomal pathways. Thus, this study reveals a complicated interplay between host restrictive factor GBP5 and RSV infection and provides important information for understanding the pathogenesis of RSV.IMPORTANCE RSV is a highly contagious virus that causes multiple infections in infants within their first year of life. It can also easily cause infection in elderly or immunocompromised individuals, suggesting that individual differences in immunity play an important role in RSV infection. Therefore, exploring the pathogenic mechanisms of RSV and identifying essential genes which inhibit RSV infection are necessary to develop an effective strategy to control RSV infection. Here, we report that the IFN-inducible gene GBP5 potently inhibits RSV replication by reducing the cell-associated levels of the RSV small hydrophobic (SH) protein, which is a viroporin. In contrast, the RSV G protein was shown to upregulate the expression of the DZIP3 protein, an E3 ligase that degrades GBP5 through the proteasomal pathway. Our study provides important information for the understanding of the pathogenic mechanisms of RSV and host immunity as well as the complicated interplay between the virus and host.


Assuntos
Proteínas de Ligação ao GTP/genética , Interações Hospedeiro-Patógeno/genética , Interferon gama/genética , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Humano/genética , Proteínas Oncogênicas de Retroviridae/genética , Adulto , Criança , Células Epiteliais/imunologia , Células Epiteliais/virologia , Feminino , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Complexo de Golgi/imunologia , Complexo de Golgi/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Inflamassomos/genética , Inflamassomos/imunologia , Interferon gama/imunologia , Masculino , Mutação , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/crescimento & desenvolvimento , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Oncogênicas de Retroviridae/imunologia , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia
4.
Eur J Immunol ; 50(10): 1591-1597, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32470143

RESUMO

Mice bearing CT26 tumors can be cured by administration of L19-mIL12 or F8-mTNF, two antibody fusion proteins which selectively deliver their cytokine payload to the tumor. In both settings, cancer cures crucially depended on CD8+ T cells and the AH1 peptide (derived from the gp70 protein of the murine leukemia virus) acted as the main tumor-rejection antigen, with ∼50% of CD8+ T cells in the neoplastic mass being AH1-specific after therapy. In order to characterize the clonality of the T cell response, its phenotype, and activation status, we isolated CD8+ T cells from tumors and secondary lymphoid organs and submitted them to T cell receptor (TCR) and total mRNA sequencing. We found an extremely diverse repertoire of more than 40 000 unique TCR sequences, but the ten most abundant TCRs accounted for >60% of CD8+ T-cell clones in the tumor. AH1-specific TCRs were consistently found among the most abundant sequences. AH1-specific T cells in the tumor had a tissue-resident memory phenotype. Treatment with L19-mIL12 led to overexpression of IL-12 receptor and of markers of cell activation and proliferation. These data suggest that the antitumor response driven by antibody-cytokine fusions proceeds through an oligoclonal expansion and activation of tumor-infiltrating CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colo/patologia , Neoplasias do Colo/terapia , Imunoterapia/métodos , Vírus da Leucemia Murina/genética , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Memória Imunológica , Interleucina-12/uso terapêutico , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/genética , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/genética , Proteínas Oncogênicas de Retroviridae/genética , Proteínas Oncogênicas de Retroviridae/imunologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia
5.
Int J Hematol ; 111(6): 803-811, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32020505

RESUMO

The prognosis of cardiac light-chain (AL) amyloidosis is considered to be very poor. We studied the treatment efficacy and outcomes by retrospectively analyzing the clinical results of 45 patients with cardiac AL amyloidosis treated at our hospital between September 2008 and March 2016. The group of patients analyzed included 29 males and 16 females with a median age of 68 years. Their baseline median NT-proBNP, cTnT, and dFLC were 3167 pg/ml, 0.080 ng/ml, and 286.17 mg/l, respectively. Twenty-eight patients were in Cardiac Stage (CS) III and 17 patients were in Revised Prognostic Stage (RPS) IV. At the median follow-up of 10 months, the median overall survival (OS) was 16 months and 3-year OS was 35.9%. The patients in CS III showed significantly poorer survival rate than those in CS I or II (3-year OS: 12.2% vs. 65.8%, p = 0.0115) and the patients in RPS IV showed significantly poorer survival rate than those in RPS I, II, or III (3-year OS: 11.0% vs. 53.3%, p = 0.000914). Regardless of the therapeutic approaches, patients who achieved hematological CR or cardiac organ response demonstrated significantly improved prognosis. Therefore, achievement of hematological and organ responses is important in the treatment of cardiac AL amyloidosis.


Assuntos
Bortezomib/administração & dosagem , Cardiomiopatias/terapia , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Melfalan/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cardiomiopatias/diagnóstico , Cardiomiopatias/mortalidade , Quimioterapia Combinada , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Japão , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prognóstico , Estudos Retrospectivos , Proteínas Oncogênicas de Retroviridae , Índice de Gravidade de Doença
6.
Retrovirology ; 16(1): 25, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492165

RESUMO

Of the members of the primate T cell lymphotropic virus (PTLV) family, only the human T-cell leukemia virus type-1 (HTLV-1) causes disease in humans-as the etiological agent of adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other auto-inflammatory disorders. Despite having significant genomic organizational and structural similarities, the closely related human T-cell lymphotropic virus type-2 (HTLV-2) is considered apathogenic and has been linked with benign lymphoproliferation and mild neurological symptoms in certain infected patients. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infections in vivo. The conserved pX sequences of HTLV-1 and HTLV-2 encode several ancillary factors which have been shown to negatively regulate proviral gene expression, while simultaneously activating host cellular proliferative and pro-survival pathways. In particular, the ORF-II proteins, HTLV-1 p30II and HTLV-2 p28II, suppress Tax-dependent transactivation from the viral promoter-whereas p30II also inhibits PU.1-mediated inflammatory-signaling, differentially augments the expression of p53-regulated metabolic/pro-survival genes, and induces lymphoproliferation which could promote mitotic proviral replication. The ubiquitinated form of the HTLV-1 p13II protein localizes to nuclear speckles and interferes with recruitment of the p300 coactivator by the viral transactivator Tax. Further, the antisense-encoded HTLV-1 HBZ and HTLV-2 APH-2 proteins and mRNAs negatively regulate Tax-dependent proviral gene expression and activate inflammatory signaling associated with enhanced T-cell lymphoproliferation. This review will summarize our current understanding of the pX latency-maintenance factors of HTLV-1 and HTLV-2 and discuss how these products may contribute to the differences in pathogenicity between the human PTLVs.


Assuntos
Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 2 Humano/genética , Fatores de Transcrição/genética , Proteínas Virais Reguladoras e Acessórias/genética , Latência Viral , Regulação Viral da Expressão Gênica , Infecções por HTLV-I/complicações , Infecções por HTLV-II/virologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Vírus Linfotrópico T Tipo 2 Humano/patogenicidade , Humanos , Vírus Linfotrópico T Tipo 1 de Primatas/genética , Vírus Linfotrópico T Tipo 1 de Primatas/patogenicidade , Proteínas Oncogênicas de Retroviridae/genética , Proteínas Oncogênicas de Retroviridae/metabolismo
7.
PLoS Pathog ; 15(4): e1007689, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30964929

RESUMO

NOD-like receptor protein 3 (NLRP3) inflammasome activation triggers caspase-1 activation-induced maturation of interleukin (IL)-1ß and IL-18 and therefore is important for the development of the host defense against various RNA viral diseases. However, the implication of this protein complex in human metapneumovirus (HMPV) disease has not been fully studied. Herein, we report that NLRP3 inflammasome plays a detrimental role during HMPV infection because NLRP3 inflammasome inhibition protected mice from mortality and reduced weight loss and inflammation without impacting viral replication. We also demonstrate that NLRP3 inflammasome exerts its deleterious effect via IL-1ß production since we observed reduced mortality, weight loss and inflammation in IL-1ß-deficient (IL-1ß-/-) mice, as compared to wild-type animals during HMPV infection. Moreover, the effect on these evaluated parameters was not different in IL-1ß-/- and wild-type mice treated with an NLRP3 inflammasome inhibitor. The production of IL-1ß was also abrogated in bone marrow derived macrophages deficient for NLRP3. Finally, we show that small hydrophobic protein-deleted recombinant HMPV (HMPV ΔSH) failed to activate caspase-1, which is responsible for IL-1ß cleavage and maturation. Furthermore, HMPV ΔSH-infected mice had less weight loss, showed no mortality and reduced inflammation, as compared to wild-type HMPV-infected mice. Thus, NLRP3 inflammasome activation seems to be triggered by HMPV SH protein in HMPV disease. In summary, once activated by the HMPV SH protein, NLRP3 inflammasome promotes the maturation of IL-1ß, which exacerbates HMPV-induced inflammation. Therefore, the blockade of IL-1ß production by using NLRP3 inflammasome inhibitors might be a novel potential strategy for the therapy and prevention of HMPV infection.


Assuntos
Inflamassomos/imunologia , Inflamação/imunologia , Interleucina-1beta/fisiologia , Metapneumovirus/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Infecções por Paramyxoviridae/imunologia , Proteínas Oncogênicas de Retroviridae/metabolismo , Animais , Feminino , Humanos , Inflamassomos/metabolismo , Inflamação/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Paramyxoviridae/virologia , Proteínas Recombinantes/metabolismo , Proteínas Oncogênicas de Retroviridae/imunologia , Transdução de Sinais , Replicação Viral
8.
Aust Vet J ; 97(3): 47-55, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30809813

RESUMO

With the commercial release in Australia in 2004 of a vaccine against feline immunodeficiency virus (FIV; Fel-O-Vax FIV®), the landscape for FIV diagnostics shifted substantially. Point-of-care (PoC) antibody detection kits, which had been the mainstay for diagnosing FIV infection since the early 1990s, were no longer considered accurate to use in FIV-vaccinated cats, because of the production of vaccine-induced antibodies that were considered indistinguishable from those produced in natural FIV infections. Consequently, attention shifted to alternative diagnostic methods such as nucleic acid detection. However, over the past 5 years we have published a series of studies emphasising that FIV PoC test kits vary in their methodology, resulting in differing accuracy in FIV-vaccinated cats. Importantly, we demonstrated that two commercially available FIV antibody test kits (Witness™ and Anigen Rapid™) were able to accurately distinguish between FIV-vaccinated and FIV-infected cats, concluding that testing with either kit offers an alternative to PCR testing. This review summarises pertinent findings from our work published in a variety of peer-reviewed research journals to inform veterinarians (particularly veterinarians in Australia, New Zealand and Japan, where the FIV vaccine is currently commercially available) about how the approach to the diagnosis of FIV infection has shifted. Included in this review is our work investigating the performance of three commercially available FIV PoC test kits in FIV-vaccinated cats and our recommendations for the diagnosis of FIV infection; the effect of primary FIV vaccination (three FIV vaccines, 4 weeks apart) on PoC test kit performance; our recommendations regarding annual testing of FIV-vaccinated cats to detect 'vaccine breakthroughs'; and the potential off-label use of saliva for the diagnosis of FIV infection using some FIV PoC test kits. We also investigated the accuracy of the same three brands of test kits for feline leukaemia virus (FeLV) diagnosis, using both blood and saliva as diagnostic specimens. Based on these results, we discuss our recommendations for confirmatory testing when veterinarians are presented with a positive FeLV PoC test kit result. Finally, we conclude with our results from the largest and most recent FIV and FeLV seroprevalence study conducted in Australia to date.


Assuntos
Síndrome de Imunodeficiência Adquirida Felina/diagnóstico , Vírus da Imunodeficiência Felina/isolamento & purificação , Vírus da Leucemia Felina/isolamento & purificação , Leucemia Felina/diagnóstico , Animais , Anticorpos Antivirais/análise , Anticorpos Antivirais/sangue , Austrália/epidemiologia , Gatos , Síndrome de Imunodeficiência Adquirida Felina/epidemiologia , Síndrome de Imunodeficiência Adquirida Felina/prevenção & controle , Vírus da Imunodeficiência Felina/imunologia , Vírus da Leucemia Felina/imunologia , Leucemia Felina/epidemiologia , Leucemia Felina/prevenção & controle , Sistemas Automatizados de Assistência Junto ao Leito , Reação em Cadeia da Polimerase , Proteínas Oncogênicas de Retroviridae/imunologia , Saliva/virologia , Sensibilidade e Especificidade , Vacinas Virais/imunologia
9.
J Virol ; 92(20)2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30068647

RESUMO

J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in 1972. It is a paramyxovirus classified under the newly proposed genus Jeilongvirus JPV has a genome of 18,954 nucleotides, consisting of eight genes in the order 3'-N-P/V/C-M-F-SH-TM-G-L-5'. JPV causes little cytopathic effect (CPE) in tissue culture cells but severe disease in mice. The small hydrophobic (SH) protein is an integral membrane protein encoded by many paramyxoviruses, such as mumps virus (MuV) and respiratory syncytial virus (RSV). However, the function of SH has not been defined in a suitable animal model. In this work, the functions of SH of JPV, MuV, and RSV have been examined by generating recombinant JPV lacking the SH protein (rJPV-ΔSH) or replacing SH of JPV with MuV SH (rJPV-MuVSH) or RSV SH (rJPV-RSVSH). rJPV-ΔSH, rJPV-MuVSH, and rJPV-RSVSH were viable and had no growth defect in tissue culture cells. However, more tumor necrosis factor alpha (TNF-α) was produced during rJPV-ΔSH infection, confirming the role of SH in inhibiting TNF-α production. rJPV-ΔSH induced more apoptosis in tissue culture cells than rJPV, rJPV-MuVSH, and rJPV-RSVSH, suggesting that SH plays a role in blocking apoptosis. Furthermore, rJPV-ΔSH was attenuated in mice compared to rJPV, rJPV-MuVSH, and rJPV-RSVSH, indicating that the SH protein plays an essential role in virulence. The results indicate that the functions of MuV SH and RSV SH are similar to that of JPV SH even though they have no sequence homology.IMPORTANCE Paramyxoviruses are associated with many devastating diseases in animals and humans. J paramyxovirus (JPV) was isolated from moribund mice in Australia in 1972. Newly isolated viruses, such as Beilong virus (BeiPV) and Tailam virus (TlmPV), have genome structures similar to that of JPV. A new paramyxovirus genus, Jeilongvirus, which contains JPV, BeiPV, and TlmPV, has been proposed. Small hydrophobic (SH) protein is present in many paramyxoviruses. Our present study investigates the role of SH protein of JPV in pathogenesis in its natural host. Understanding the pathogenic mechanism of Jeilongvirus is important to control and prevent potential diseases that may emerge from this group of viruses.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Infecções por Paramyxoviridae/patologia , Paramyxoviridae/crescimento & desenvolvimento , Proteínas Oncogênicas de Retroviridae/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fatores de Virulência/metabolismo , Animais , Linhagem Celular , Chlorocebus aethiops , Modelos Animais de Doenças , Deleção de Genes , Teste de Complementação Genética , Humanos , Camundongos , Viabilidade Microbiana , Vírus da Caxumba/genética , Vírus da Caxumba/fisiologia , Infecções por Paramyxoviridae/virologia , Vírus Sinciciais Respiratórios/genética , Vírus Sinciciais Respiratórios/fisiologia , Proteínas Oncogênicas de Retroviridae/genética , Virulência , Fatores de Virulência/genética
10.
Viruses ; 10(6)2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29789500

RESUMO

Human metapneumovirus (hMPV), a leading cause of respiratory tract infections in infants, encodes a small hydrophobic (SH) protein of unknown function. Here we show that infection of plasmacytoid dendritic cells (pDCs) with a recombinant virus lacking SH expression (rhMPV-ΔSH) enhanced the secretion of type I interferons (IFNs), which required TLR7 and MyD88 expression. HMPV SH protein inhibited TLR7/MyD88/TRAF6 signaling leading to IFN gene transcription, identifying a novel mechanism by which paramyxovirus SH proteins modulate innate immune responses.


Assuntos
Células Dendríticas/virologia , Interferon Tipo I/metabolismo , Metapneumovirus/genética , Proteínas Oncogênicas de Retroviridae/imunologia , Células Dendríticas/imunologia , Células HEK293 , Humanos , Imunidade Inata , Metapneumovirus/fisiologia , Fator 88 de Diferenciação Mieloide/imunologia , Transdução de Sinais , Receptor 7 Toll-Like/imunologia
11.
Virol J ; 15(1): 80, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29716616

RESUMO

BACKGROUND: The human T-lymphotropic virus type 1 (HTLV-1) affects 2-5 million people worldwide, and is associated with a number of degenerative and infectious diseases. The Envelope glycoproteins (gp) are highly conserved among the different HTLV-1 isolates, although nucleotide substitutions in the region that codifies these proteins may influence both the infectivity and the replication of the virus. The gp46 gene has functional domains which have been associated with the inhibition of the formation of the syncytium, cell-cell transmission, and the production of antibodies. The present study investigated the genetic stability of the gp46 gene of HTLV-1 in an endemic region of Brazilian Amazonia. METHODS: Index case (IC - a sample of a given family group) carriers of HTLV-1 were investigated in the metropolitan region of Belém (Pará, Brazil) between January 2010 (registered retrospectively) and December 2015. The sequences that codify the gp46 were amplified by PCR, purified and sequenced (MF084788-MF084825). The gene was characterized using bioinformatics and Bayesian Inference. RESULTS: The 40 patients analyzed had a mean age of 45.2 years and 70% presented some type of symptom, with a predominance of pain and sensitivity, dysautonomia, and motor disorders. All patients presented the aA (Transcontinental Cosmopolitan) genotype, with an extremely low mutation rate, which is characteristic of the codifying region (aA - 1.83 × 10-4 mutations per site per year). The gp46 gene had a nucleotide diversity of between 0.00% and 2.0%. Amino acid mutations were present in 66.6% of the samples of individuals with signs/symptoms or diseases associated with HTLV-1 (p = 0.0091). Of the three most frequent mutations, the previously undescribed N93D mutant was invariably associated with symptomatic cases. CONCLUSIONS: The aA HTLV-1 subtype is predominant in the metropolitan region of Belém and presented a high degree of genetic stability in the codifying region. The rare N93D amino acid mutation may be associated with the clinical manifestations of this viral infection. IMPORTANCE: Little is known of the phylogeny of HTLV-1 in the endemic region of Brazilian Amazonia, and few complete gene sequences are available for the gp46 glycoprotein from the local population. The nucleotide sequences of the viral gp46 gene recorded in the present study confirmed the genetic stability of the region, and pointed to a homogeneous viral group, with local geographic characteristics. Further research will be necessary to more fully understand the molecular diversity of this protein, given the potential of this codifying region as a model for an effective HTLV-1 vaccine. The identification of a rare mutation (N93D), present only in symptomatic patients, should also be investigated further as a potential clinical marker. TRIAL REGISTRATION: ISRCTN 12345678, registered 28 September 2014.


Assuntos
Doenças Endêmicas , Produtos do Gene env/genética , Infecções por HTLV-I/epidemiologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Mutação , Dor/epidemiologia , Disautonomias Primárias/epidemiologia , Proteínas Oncogênicas de Retroviridae/genética , Adulto , Substituição de Aminoácidos , Sequência de Bases , Teorema de Bayes , Brasil/epidemiologia , Biologia Computacional , Feminino , Expressão Gênica , Genótipo , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-I/fisiopatologia , Infecções por HTLV-I/virologia , Heterozigoto , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Dor/diagnóstico , Dor/fisiopatologia , Dor/virologia , Disautonomias Primárias/diagnóstico , Disautonomias Primárias/fisiopatologia , Disautonomias Primárias/virologia , Domínios Proteicos , Estudos Retrospectivos , Análise de Sequência de DNA
12.
Iran J Allergy Asthma Immunol ; 17(2): 144-150, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29757587

RESUMO

We aimed to develope a peptide-based indirect ELISA to detect antibodies against Human T-lymphotropic virus type I (HTLV-I). Two chimeric peptides (CP-1 and CP-2) were designed using linear immunodominant epitopes of gp-46-I, and gp21-I proteins, according to the sequence from Uniprot database. These peptides were studied initially in the ELISA using infected sera. The most promising peptideCP-1, was used to develop a peptide ELISA for detection of HTLV-I infected sera. The optimal conditions for CP-1ELISA were: the optimum coating buffer was 100mM NaHCO3, pH 9.6; coating peptide concentration was 10 µg/mL; the optimal blocking buffer was5% fetal bovine serum (FBS); the secondary antibody concentration was 1:2000; and serum dilution was 1:20. 20serum samples from HTLV-I infected patients were evaluated by ELISA developed. CP-1 showed high antigenicity while lacking any cross-reactivity with normal human sera. The results of evaluations indicated that in comparison with commercial ELISA, CP-1 ELISA showed good sensitivity and specificity. With further validation, CP-1as described in the present study could be introduced as novel reliable and cost-effective candidates for the high-specific screening of HTLV-I/-II infections in endemic regions.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Produtos do Gene env/química , Anticorpos Anti-HTLV-I/sangue , Infecções por HTLV-I/diagnóstico , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Peptídeos/imunologia , Proteínas Oncogênicas de Retroviridae/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Sequência de Aminoácidos , Produtos do Gene env/imunologia , Antígenos HTLV-I/química , Antígenos HTLV-I/imunologia , Infecções por HTLV-I/sangue , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Epitopos Imunodominantes/química , Epitopos Imunodominantes/imunologia , Peptídeos/síntese química , Peptídeos/química , Proteínas Oncogênicas de Retroviridae/imunologia , Sensibilidade e Especificidade , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
13.
J Infect Dis ; 218(3): 378-387, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29617814

RESUMO

Background: Respiratory syncytial virus infection can cause lower respiratory tract infection in older adults comparable to influenza, but no vaccines are available. Methods: This was a randomized, observer-blinded, first-in-humans study of a novel synthetic RSV antigen based on the ectodomain of the small hydrophobic glycoprotein (SHe) of RSV subgroup A, formulated with either the lipid and oil-based vaccine platform DepoVax (DPX-RSV[A]) or alum (RSV[A]-Alum), in healthy, 50-64-year-old individuals. Two dose levels (10 or 25 µg) of SHe with each formulation were compared to placebo. A booster dose was administered on day 56. Results: There was no indication that the vaccine was unsafe. Mild pain, drowsiness, and muscles aches were the most common solicited adverse events (AEs), and the frequencies of the AEs did not increase after dose 2. Robust anti-SHe-specific immune responses were demonstrated in the DPX-RSV(A) 10-µg and 25-µg groups (geometric mean titer, approximately 10-fold and 100-fold greater than that of placebo at days 56 and 236, respectively), and responses were sustained in the DPX-RSV(A) 25-µg group at day 421. Responses to the RSV(A)-Alum vaccines were very low. Conclusions: A novel antigen from the SH protein of RSV, formulated in a lipid and oil-based vaccine platform, was highly immunogenic, with sustained antigen-specific antibody responses, and had an acceptable safety profile.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/sangue , Lipídeos/administração & dosagem , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Oncogênicas de Retroviridae/imunologia , Compostos de Alúmen/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Humanos , Imunidade Humoral , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Método Simples-Cego , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/imunologia
14.
Biochim Biophys Acta Proteins Proteom ; 1866(4): 541-548, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29458191

RESUMO

Entry of human T-cell lymphotropic virus type 1 (HTLV-1) into host cells is mainly mediated by interactions between the viral envelope glycoprotein surface unit (SU) and three host receptors: glucose transporter type 1, heparin/heparan sulfate proteoglycan, and neuropilin-1 (Nrp1). Here, we analyzed the interaction between HTLV-1 SU and Nrp1 using nuclear magnetic resonance and isothermal titration calorimetry. We found that two SU peptides, residues 85-94 and residues 304-312, bound directly to the Nrp1 b1 domain with affinities of 7.4 and 17.7 µM, respectively. The binding modes of both peptides were almost identical to those observed for Tuftsin and vascular endothelial growth factor A binding to the Nrp1 b1 domain. These results suggest that the C-terminal region of HTLV-1 SU contains a novel site for direct binding of virus to the Nrp1 b1 domain. Our biophysical characterization of the SU peptides may help in developing inhibitors of HTLV-1 entry.


Assuntos
Produtos do Gene env/química , Vírus Linfotrópico T Tipo 1 Humano/química , Neuropilina-1/química , Proteínas Oncogênicas de Retroviridae/química , Sítios de Ligação , Produtos do Gene env/genética , Produtos do Gene env/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Neuropilina-1/genética , Neuropilina-1/metabolismo , Ligação Proteica , Proteínas Oncogênicas de Retroviridae/genética , Proteínas Oncogênicas de Retroviridae/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-28861397

RESUMO

The Human Respiratory Syncytial Virus (hRSV) is a major cause of acute lower respiratory tract infections (ARTIs) and high rates of hospitalizations in children and in the elderly worldwide. Symptoms of hRSV infection include bronchiolitis and pneumonia. The lung pathology observed during hRSV infection is due in part to an exacerbated host immune response, characterized by immune cell infiltration to the lungs. HRSV is an enveloped virus, a member of the Pneumoviridae family, with a non-segmented genome and negative polarity-single RNA that contains 10 genes encoding for 11 proteins. These include the Fusion protein (F), the Glycoprotein (G), and the Small Hydrophobic (SH) protein, which are located on the virus surface. In addition, the Nucleoprotein (N), Phosphoprotein (P) large polymerase protein (L) part of the RNA-dependent RNA polymerase complex, the M2-1 protein as a transcription elongation factor, the M2-2 protein as a regulator of viral transcription and (M) protein all of which locate inside the virion. Apart from the structural proteins, the hRSV genome encodes for the non-structural 1 and 2 proteins (NS1 and NS2). HRSV has developed different strategies to evade the host immunity by means of the function of some of these proteins that work as virulence factors to improve the infection in the lung tissue. Also, hRSV NS-1 and NS-2 proteins have been shown to inhibit the activation of the type I interferon response. Furthermore, the hRSV nucleoprotein has been shown to inhibit the immunological synapsis between the dendritic cells and T cells during infection, resulting in an inefficient T cell activation. Here, we discuss the hRSV virulence factors and the host immunological features raised during infection with this virus.


Assuntos
Imunidade Adaptativa , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Virais/imunologia , Fatores de Virulência/imunologia , Idoso , Criança , Células Dendríticas/imunologia , Genoma Viral , Glicoproteínas/genética , Humanos , Evasão da Resposta Imune , Sinapses Imunológicas/imunologia , Interferon Tipo I/metabolismo , Interferons/imunologia , Pulmão/patologia , Ativação Linfocitária , Nucleoproteínas/genética , Fosfoproteínas/genética , RNA Polimerase Dependente de RNA/genética , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/patogenicidade , Vírus Sincicial Respiratório Humano/fisiologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Proteínas Oncogênicas de Retroviridae/genética , Linfócitos T/imunologia , Proteínas Virais de Fusão/genética , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Virais/fisiologia , Proteínas Estruturais Virais/genética , Proteínas Estruturais Virais/metabolismo , Fatores de Virulência/genética , Fatores de Virulência/fisiologia
16.
J Gen Virol ; 98(7): 1587-1599, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28714847

RESUMO

Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease in young cattle and is closely related to human RSV (HRSV), which causes severe respiratory disease in infants and the elderly. The RSV genome encodes a small hydrophobic (SH) protein with viroporin activity. Previous studies have shown that recombinant BRSV lacking the SH gene (rBRSVΔSH) is attenuated in the lungs, but not in the upper respiratory tract, of calves and mucosal vaccination with rBRSVΔSH induced long-lasting protective immunity. Attenuation of rBRSVΔSH may be due to the ability of this virus to induce an early innate response as rBRSVΔSH induces higher levels of pro-inflammatory cytokines than wild-type (wt) rBRSV. In this study, we investigated the effects of the BRSV SH protein on NF-κB p65 phosphorylation, a master step in the regulation of pro-inflammatory cytokines. Expression of SH resulted in the inhibition of NF-κB p65 phosphorylation in response to BRSV infection and extracellular lipopolysaccharide, and a reduction in the production of pro-inflammatory cytokines. In contrast, rBRSVΔSH does not inhibit NF-κB p65 phosphorylation in bovine antigen-presenting cells, including monocytes, macrophages and dendritic cells, resulting in increased expression of pro-inflammatory cytokines and increased activation of T cells compared to cells infected with wt BRSV. These findings highlight an important role for the BRSV SH protein in immune modulation.


Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Vírus Sincicial Respiratório Bovino/metabolismo , Proteínas Oncogênicas de Retroviridae/imunologia , Fator de Transcrição RelA/metabolismo , Animais , Bovinos , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/virologia , Linhagem Celular , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Humanos , Lipopolissacarídeos/metabolismo , Ativação Linfocitária/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Monócitos/metabolismo , Monócitos/virologia , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação , Células RAW 264.7 , Vírus Sincicial Respiratório Bovino/genética , Vírus Sincicial Respiratório Bovino/imunologia , Proteínas Oncogênicas de Retroviridae/genética , Proteínas Oncogênicas de Retroviridae/metabolismo , Linfócitos T/imunologia
17.
AIDS ; 30(16): 2427-2438, 2016 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-27428745

RESUMO

Vaccination with SIVmac239Δnef provides robust protection against subsequent challenge with wild-type simian immunodeficiency virus (SIV), but safety issues have precluded designing an HIV-1 vaccine based on a live-attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIVmac239Δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-monophosphoryl lipid A adjuvant liposomal nanoparticle for intramuscular (i.m.) immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn+ cervical vaginal epithelium, thus recapitulating one key feature of SIVmac239Δnef vaccinated and protected animals. Although this strategy did not reproduce the system of local production of antibody in SIVmac239Δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization.


Assuntos
Anticorpos Antivirais/imunologia , Produtos do Gene env/imunologia , Proteínas Oncogênicas de Retroviridae/imunologia , Vacinas contra a SAIDS/imunologia , Vírus da Imunodeficiência Símia/imunologia , Proteínas Virais de Fusão/imunologia , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Epitélio/imunologia , Produtos do Gene env/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade nas Mucosas , Injeções Intramusculares , Lipídeo A/administração & dosagem , Macaca mulatta , Camundongos Endogâmicos BALB C , Coelhos , Receptores Fc/imunologia , Proteínas Oncogênicas de Retroviridae/genética , Vacinas contra a SAIDS/administração & dosagem , Vacinas contra a SAIDS/genética , Vírus da Imunodeficiência Símia/genética , Proteínas Virais de Fusão/genética
18.
J Neuroinflammation ; 13(1): 144, 2016 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-27287400

RESUMO

BACKGROUND: Elevated levels of oncostatin M (OSM), an interleukin-6 cytokine family member, have been observed in HIV-1-associated neurocognitive disorders (HAND) and Alzheimer's disease. However, the function of OSM in these disease conditions is unclear. Since deficient glutamate uptake by astrocytes is instrumental in HAND-associated neurotoxicity, we hypothesized that OSM impairs glutamate uptake in astrocytes and thereby promotes neuronal excitotoxicity. METHODS: Primary cultures of mouse cortical astrocytes, neurons, microglia, and BV2 cell line were used. The expression of glutamate transporters (GLAST/EAAT1 and GLT-1/EAAT2) was investigated using real-time PCR and Western blot, and their activity was assessed by measuring (3)H-D-aspartate uptake. Neuronal toxicity was measured using the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl-) 2,5-diphenyltetrazolium bromide) assay and immunocytochemistry. A chimeric HIV-1 that infects murine cells (EcoHIV/NL4-3-GFP virus (EcoHIV)) was used to investigate whether the virus induces OSM, OSM receptor (OSMR)-ß, glycoprotein 130 (gp130), GLT-1, GLAST (mRNA and protein), and OSM release (ELISA) in cultured BV2 cells, primary microglia, or astrocytes. Statistical analyses of the data were performed using one-way ANOVA (to allow multiple comparisons) and two-tailed Student's t test. RESULTS: OSM treatment (10 ng/mL) time-dependently reduced GLAST and GLT-1 expression and inhibited (3)H-D-aspartate uptake in cultured astrocytes in a concentration-dependent manner, an effect prevented by the Janus kinase (JAK)/signal transducers and activators of transcription (STAT)3 inhibitor AG490. Down-regulation of astrocytic glutamate transport by OSM resulted in NMDA receptor-dependent excitotoxicity in cortical neurons. Infection with EcoHIV induced OSM gene expression and protein release in BV2 cells and microglia, but not in astrocytes. Conversely, EcoHIV caused a fivefold increase in OSMR-ß mRNA (but not gp130) and protein in astrocytes, but not in microglia, which did not express OSMR-ß protein. Finally, astrocytic expression of GLAST gene was unaffected by EcoHIV, whereas GLT-1 mRNA was increased by twofold. CONCLUSIONS: We provide first evidence that activation of JAK/STAT3 signaling by OSM inhibits glutamate uptake in astrocytes, which results in neuronal excitotoxicity. Our findings with EcoHIV suggest that targeting OSMR-ß signaling in astrocytes might alleviate HIV-1-associated excitotoxicity.


Assuntos
Antineoplásicos/efeitos adversos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Oncostatina M/efeitos adversos , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Ácido Aspártico/metabolismo , Astrócitos/virologia , Células Cultivadas , Córtex Cerebral/citologia , Citocinas/genética , Citocinas/metabolismo , Embrião de Mamíferos , Agonistas de Aminoácidos Excitatórios/toxicidade , Transportador 2 de Aminoácido Excitatório/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oncostatina M/farmacologia , Subunidade beta de Receptor de Oncostatina M/metabolismo , Proteínas Oncogênicas de Retroviridae/toxicidade , Transdução de Sinais/efeitos dos fármacos
19.
Microb Pathog ; 97: 38-44, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27235335

RESUMO

To prevent the spread of HTLV-I (Human T-lymphotropic virus type 1), a safe and effective vaccine is required. To increase immune responses against the peptide antigens can be potentiated with polymer-based nanoparticles, like chitosan (CHT) and trimethylchitosan (TMC), as delivery system/adjuvant. CHT and TMC nanoparticles loaded with recombinant proteins (env23 & env13) of gp46 were prepared by direct coating of antigens with positively charged polymers. The size of CHT and TMC nanoparticles (NPs) loaded with each antigen was about 400 nm. The physical stability of NPs was followed for 4 weeks. Both formulations showed to be stable for about 15 days. The immunogenicity of NPs loaded with antigens was studied after nasal and subcutaneous immunization in mice. Three immunizations (7.5 µg antigen) were performed with 2 weeks intervals. Two weeks after the last booster dose, sera IgG subtypes were measured. After subcutaneous administration, for both nanoparticulate antigens, serum IgG1 and IgGtotal levels were higher than antigen solution (P < 0.001). After nasal administration, for env23, IgG2a levels and IgG2a/IgG1 ratio was significantly higher than groups with subcutaneous administration (P < 0.001). Both nanoparticles showed good immunoadjuvant potential. Env23 antigen was a better candidate for vaccination against HTLV-I, as it induced higher cellular immune responses, compared with env13.


Assuntos
Antígenos Virais/imunologia , Quitosana/administração & dosagem , Produtos do Gene env/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Nanopartículas/administração & dosagem , Proteínas Oncogênicas de Retroviridae/imunologia , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/genética , Portadores de Fármacos/administração & dosagem , Estabilidade de Medicamentos , Produtos do Gene env/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Imunoglobulina G/sangue , Injeções Subcutâneas , Masculino , Camundongos Endogâmicos BALB C , Proteínas Oncogênicas de Retroviridae/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
20.
Adv Protein Chem Struct Biol ; 104: 307-355, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27038378

RESUMO

Since the discovery that certain small viral membrane proteins, collectively termed as viroporins, can permeabilize host cellular membranes and also behave as ion channels, attempts have been made to link this feature to specific biological roles. In parallel, most viroporins identified so far are virulence factors, and interest has focused toward the discovery of channel inhibitors that would have a therapeutic effect, or be used as research tools to understand the biological roles of viroporin ion channel activity. However, this paradigm is being shifted by the difficulties inherent to small viral membrane proteins, and by the realization that protein-protein interactions and other diverse roles in the virus life cycle may represent an equal, if not, more important target. Therefore, although targeting the channel activity of viroporins can probably be therapeutically useful in some cases, the focus may shift to their other functions in following years. Small-molecule inhibitors have been mostly developed against the influenza A M2 (IAV M2 or AM2). This is not surprising since AM2 is the best characterized viroporin to date, with a well-established biological role in viral pathogenesis combined the most extensive structural investigations conducted, and has emerged as a validated drug target. For other viroporins, these studies are still mostly in their infancy, and together with those for AM2, are the subject of the present review.


Assuntos
Membrana Celular/metabolismo , Canais Iônicos/genética , Mapas de Interação de Proteínas , Proteínas do Envelope Viral/metabolismo , Membrana Celular/genética , Humanos , Canais Iônicos/metabolismo , Proteínas Oncogênicas de Retroviridae/metabolismo , Proteínas da Matriz Viral/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo
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