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1.
Mucosal Immunol ; 11(5): 1342-1351, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29875402

RESUMO

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4ß7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4ß7. Such costimulation promotes high levels of HIV replication. An anti-α4ß7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4ß7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α4ß7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4ß7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.


Assuntos
Infecções por HIV/metabolismo , HIV/fisiologia , Integrinas/metabolismo , Replicação Viral/fisiologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/virologia , Feminino , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Memória Imunológica/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Tecido Linfoide/metabolismo , Tecido Linfoide/virologia , Macaca mulatta , Domínios e Motivos de Interação entre Proteínas , Receptores CCR5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tretinoína/metabolismo , Regulação para Cima/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
2.
J Acquir Immune Defic Syndr ; 75(1): 118-127, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28177967

RESUMO

The homing of lymphocytes to the mucosa is mainly controlled by α4ß7 integrin, and it is amplified during gut chronic inflammation, as occurs with HIV and/or inflammatory bowel diseases. We designed and applied an improved immunization strategy based on an innovative selection process to isolate new α4ß7 lymphocyte-specific monoclonal antibodies that are able to prevent their migration into inflamed gut tissues and/or to counteract HIV infection in vitro. First, 5 monoclonal antibodies (1 IgA, 1 IgM, and 4 IgGs) were selected based on their capacity to recognize α4 or ß7 homodimers and α4ß7 heterodimers in transfected human cells. Their ability to block gp120/α4ß7 or MAdCAM-1/α4ß7 interactions was then measured in vitro with human T and B lymphocytes. In vitro, the anti-α4ß7 IgA isotype was found to have the highest affinity for the α4ß7 heterodimer, and it significantly reduced HIV replication in retinoic acid-treated α4ß7 CD4 human T cells. This α4ß7-specific IgA also displayed a high avidity for human and mouse α4ß7 lymphocytes in both mouse and human inflammatory colitis tissues. These new antibodies, and in particular those with mucosa-targeting isotypes such as IgA, could therefore be potential novel therapeutic tools for treating HIV and inflammatory bowel disease.


Assuntos
Linfócitos B/imunologia , Isotipos de Imunoglobulinas/imunologia , Integrinas/antagonistas & inibidores , Integrinas/imunologia , Linfócitos T/imunologia , Linfócitos T/virologia , Replicação Viral , Animais , Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , HIV/fisiologia , Humanos , Fatores Imunológicos/farmacologia , Camundongos Endogâmicos BALB C
3.
Science ; 354(6309): 197-202, 2016 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-27738167

RESUMO

Antiretroviral drug therapy (ART) effectively suppresses replication of both the immunodeficiency viruses, human (HIV) and simian (SIV); however, virus rebounds soon after ART is withdrawn. SIV-infected monkeys were treated with a 90-day course of ART initiated at 5 weeks post infection followed at 9 weeks post infection by infusions of a primatized monoclonal antibody against the α4ß7 integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4+ T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn. This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Imunização Passiva/métodos , Integrina alfa4/imunologia , Cadeias beta de Integrinas/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Viremia/terapia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Terapia Combinada , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Trato Gastrointestinal/imunologia , Infusões Intravenosas , Células Matadoras Naturais/imunologia , Macaca mulatta , Masculino , Glicoproteínas de Membrana/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/isolamento & purificação , Subpopulações de Linfócitos T/imunologia , Tretinoína/sangue , Proteínas do Envelope Viral/imunologia , Carga Viral/imunologia , Viremia/sangue , Viremia/tratamento farmacológico , Viremia/virologia
4.
Curr Drug Targets ; 17(1): 122-35, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26302793

RESUMO

Although extraordinary progress has been made in the treatment and prevention of HIV infection, the AIDS pandemic continues to rage globally with 2.1 million infections and 1.6 million AIDS-related deaths reported in 2013. Until an effective vaccine is developed, new strategies for treatment and prevention are needed. Regarding the prevention of HIV infection, a major focus of prevention research in general and vaccine research in particular involves the interaction of the HIV-1 envelope protein gp120 with cell-surface receptors, with the hope that a greater understanding of these interactions will lead to the development of novel strategies aimed at preventing and even treating HIV-1 infection. Particular attention has been directed toward gaining a more precise understanding of the early events in transmission focusing on that critical window of time when HIV first establishes infection in the host. Here we describe some of the recent findings involving HIV-1 envelope interactions with cell surface receptors that are relevant to transmission and which may represent new opportunities to develop strategies to prevent HIV infection.


Assuntos
Vacinas contra a AIDS/farmacologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV , HIV-1 , Receptores de Superfície Celular/imunologia , Descoberta de Drogas , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Transdução de Sinais/efeitos dos fármacos
5.
Nat Immunol ; 14(12): 1256-65, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24162774

RESUMO

The humoral immune response after acute infection with HIV-1 is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through integrin α4ß7 on T cells. We found that gp120 also bound to and signaled through α4ß7 on naive B cells, which resulted in an abortive proliferative response. In primary B cells, signaling by gp120 through α4ß7 resulted in increased expression of the immunosuppressive cytokine TGF-ß1 and FcRL4, an inhibitory receptor expressed on B cells. Coculture of B cells with HIV-1-infected autologous CD4(+) T cells also increased the expression of FcRL4 by B cells. Our findings indicated that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV-1-associated B cell dysfunction. Our studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Proteína gp120 do Envelope de HIV/imunologia , Receptores Fc/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células CHO , Células Cultivadas , Técnicas de Cocultura , Cricetinae , Cricetulus , Citometria de Fluxo , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/genética , HIV-1/imunologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Integrinas/genética , Integrinas/imunologia , Integrinas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica/imunologia , Receptores Fc/genética , Receptores Fc/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
6.
PLoS Pathog ; 7(2): e1001301, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21383973

RESUMO

Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α4ß7/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin-α4ß7. High-affinity for integrin α4ß7, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α4ß7 affinity is mediated by sequences encoded in gp120 V1/V2. α4ß7-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α4ß7+/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses. Understanding the structural features that characterize early-transmitting gp120s may aid in the design of an effective gp120-based subunit vaccine.


Assuntos
Linfócitos T CD4-Positivos/virologia , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/transmissão , HIV/genética , Integrinas/metabolismo , Mucosa Intestinal/virologia , Sequência de Aminoácidos , Anticorpos Neutralizantes , Células Cultivadas , Citometria de Fluxo , Genótipo , Glicosilação , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/virologia , Humanos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Ressonância de Plasmônio de Superfície
7.
Proc Natl Acad Sci U S A ; 106(49): 20877-82, 2009 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-19933330

RESUMO

Both activated and resting CD4(+) T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin alpha(4)beta(7) (alpha(4)beta(7)), the gut mucosal homing receptor. We find that alpha(4)beta(7)(high) CD4(+) T cells are more susceptible to productive infection than are alpha(4)beta(7)(low-neg) CD4(+) T cells in part because this cellular subset is enriched with metabolically active CD4(+) T cells. alpha(4)beta(7)(high) CD4(+) T cells are CCR5(high) and CXCR4(low); on these cells, alpha(4)beta(7) appears in a complex with CD4. The specific affinity of gp120 for alpha(4)beta(7) provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.


Assuntos
Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Integrinas/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Anticorpos Monoclonais/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/imunologia , Membrana Celular/virologia , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/imunologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Imunoprecipitação , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Receptores CCR5/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
8.
Mol Pharmacol ; 72(5): 1111-23, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17666592

RESUMO

We have identified two new histone deacetylase (HDAC) inhibitors (9 and 24) capable of inducing the expression of gamma-globin and/or beta-globin promoter-driven reporter genes in a synthetic model of Hb switch. Both compounds also increased, with different mechanisms, the gamma/(gamma+beta) ratio expressed in vitro by normal human erythroblasts. Compound 9 increased the levels of gamma-globin mRNA and the gamma/(gamma+beta) ratio (both by 2-fold). Compound 24 increased by 3-fold the level of gamma-globin and decreased by 2-fold that of beta-globin mRNA, increasing the gamma/(gamma+beta) ratio by 6-fold, and raising (by 50%) the cell HbF content. Both compounds raised the acetylation state of histone H4 in primary cells, an indication that their activity was mediated through HDAC inhibition. Compounds 9 and 24 were also tested as gamma/(gamma+beta) mRNA inducers in erythroblasts obtained from patients with beta(0) thalassemia. Progenitor cells from patients with beta(0) thalassemia generated in vitro morphologically normal proerythroblasts that, unlike normal cells, failed to mature in the presence of EPO and expressed low beta-globin levels but 10 times higher-than-normal levels of the alpha hemoglobin-stabilizing protein (AHSP) mRNA. Both compounds ameliorated the impaired in vitro maturation in beta(0) thalassemic erythroblasts, decreasing AHSP expression to normal levels. In the case of two patients (of five analyzed), the improved erythroblast maturation was associated with detectable increases in the gamma/(gamma+beta) mRNA ratio. The low toxicity exerted by compounds 9 and 24 in all of the assays investigated suggests that these new HDAC inhibitors should be considered for personalized therapy of selected patients with beta(0) thalassemia.


Assuntos
Inibidores Enzimáticos/farmacologia , Eritroblastos/efeitos dos fármacos , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Pirimidinonas/farmacologia , Pirróis/farmacologia , Talassemia/metabolismo , Doadores de Sangue , Inibidores Enzimáticos/química , Eritroblastos/metabolismo , Expressão Gênica/efeitos dos fármacos , Globinas/genética , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Pirimidinonas/química , Pirróis/química , Tubulina (Proteína)/metabolismo
9.
Exp Hematol ; 35(5): 735-47, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17577923

RESUMO

OBJECTIVE: To characterize how interleukin-3 and erythropoietin regulate cell fate by modulating the expression of lineage-specific transcription factors. METHODS: This study analyzed mRNA and protein levels, gene transcription rates, and mRNA and protein stabilities of erythroid-specific transcription factors in lineage-restricted cells derived from the 32D cell line cultured either in interleukin-3 or erythropoietin. RESULTS: Erythroid 32D subclones expressed levels of Idl, Gata-2, and Scl comparable and levels of Eklf and Gata-1 higher than those expressed by myeloid subclones. While maintained in interleukin-3, erythroid cells remained immature despite their high expression of Gata-1, Gata-2, Scl, Eklf, and Idl. Switching the erythroid cells to erythropoietin induced cell maturation (within 48 hours) and reduced expression of Gata-2 and Idl (in 24 hours) but did not alter the expression of Gata-1. The effects of interleukin-3 were mostly mediated by increases in transcription rates (Scl and Gata-2), and that of erythropoietin was apparently due to increased mRNA and protein (Gata-1, Scl, and Eklf) stability. In particular, erythropoietin increased the stability of the processed and transcriptionally more active form of GATA-1 protein. CONCLUSIONS: These results suggest that interleukin-3 and erythropoietin cooperate to establish the lineage-specific transcription factor milieu of erythroid cells: interleukin-3 regulates mainly gene transcription and erythropoietin consistently increases mRNA and protein stability.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Eritroides/efeitos dos fármacos , Fatores de Ligação de DNA Eritroide Específicos/metabolismo , Eritropoetina/fisiologia , Proteína 1 Inibidora de Diferenciação/metabolismo , Interleucina-3/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Células Eritroides/citologia , Fatores de Ligação de DNA Eritroide Específicos/efeitos dos fármacos , Fatores de Ligação de DNA Eritroide Específicos/genética , Eritropoetina/farmacologia , Perfilação da Expressão Gênica , Proteína 1 Inibidora de Diferenciação/efeitos dos fármacos , Proteína 1 Inibidora de Diferenciação/genética , Interleucina-3/farmacologia , Camundongos , Fenótipo , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Relação Estrutura-Atividade , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Fatores de Tempo
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