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1.
J Immunol ; 192(7): 3308-18, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24610016

RESUMO

The mucosa that lines the respiratory and gastrointestinal (GI) tracts is an important portal of entry for pathogens and provides the first line of innate immune defense against infections. Although an abundance of memory CD4(+) T cells at mucosal sites render them highly susceptible to HIV infection, the gut and not the lung experiences severe and sustained CD4(+) T cell depletion and tissue disruption. We hypothesized that distinct immune responses in the lung and gut during the primary and chronic stages of viral infection contribute to these differences. Using the SIV model of AIDS, we performed a comparative analysis of the molecular and cellular characteristics of host responses in the gut and lung. Our findings showed that both mucosal compartments harbor similar percentages of memory CD4(+) T cells and displayed comparable cytokine (IL-2, IFN-γ, and TNF-α) responses to mitogenic stimulations prior to infection. However, despite similar viral replication and CD4(+) T cell depletion during primary SIV infection, CD4(+) T cell restoration kinetics in the lung and gut diverged during acute viral infection. The CD4(+) T cells rebounded or were preserved in the lung mucosa during chronic viral infection, which correlated with heightened induction of type I IFN signaling molecules and innate viral restriction factors. In contrast, the lack of CD4(+) T cell restoration in the gut was associated with dampened immune responses and diminished expression of viral restriction factors. Thus, unique immune mechanisms contribute to the differential response and protection of pulmonary versus GI mucosa and can be leveraged to enhance mucosal recovery.


Assuntos
Citotoxicidade Imunológica/imunologia , Expressão Gênica/imunologia , Imunidade nas Mucosas/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Fator de Necrose Tumoral alfa/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citotoxicidade Imunológica/genética , Modelos Animais de Doenças , Citometria de Fluxo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade nas Mucosas/genética , Memória Imunológica/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Macaca mulatta , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , Prognóstico , Recuperação de Função Fisiológica/genética , Recuperação de Função Fisiológica/imunologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Transcriptoma/genética , Transcriptoma/imunologia , Fator de Necrose Tumoral alfa/genética
2.
PLoS Pathog ; 6(1): e1000748, 2010 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-20126442

RESUMO

The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Citotóxicos/imunologia , Viremia/imunologia , Animais , Antirretrovirais/farmacologia , Expressão Gênica , Produtos do Gene gag/biossíntese , Produtos do Gene gag/imunologia , Produtos do Gene nef/biossíntese , Produtos do Gene nef/imunologia , Macaca mulatta , Modelos Teóricos , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Carga Viral/efeitos dos fármacos
3.
J Virol ; 82(1): 538-45, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17959677

RESUMO

Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is a site for severe CD4(+) T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4(+) T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4(+) T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability to control viral replication and repair and regenerate intestinal mucosal tissues.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/fisiologia , Tecido Linfoide/imunologia , Tecido Linfoide/virologia , Macrófagos/imunologia , Macrófagos/virologia , Pessoa de Meia-Idade
4.
Clin Vaccine Immunol ; 16(2): 277-81, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19091994

RESUMO

Simian immunodeficiency virus (SIV) infection disseminated into the oropharyngeal tissues of rhesus macaques 6 weeks following intravenous inoculation. Severe local CD4(+) T-cell depletion coincided with increases in NK cell and proinflammatory biomarkers and the disruption of growth-associated gene transcription, demonstrating the rapid establishment of pathogenesis in the oral mucosa.


Assuntos
Citotoxicidade Imunológica , Mucosa Bucal/imunologia , Mucosa Bucal/virologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/patogenicidade , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Perfilação da Expressão Gênica , Humanos , Células Matadoras Naturais/imunologia , Macaca mulatta
5.
Urology ; 70(3): 608-12, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17905135

RESUMO

OBJECTIVES: To identify the relationships between key components of the proliferative and apoptotic pathways in bladder tumors. METHODS: A tissue array of 88 bladder tumors was assembled. Immunohistochemical analyses were used to investigate the relationship between nine different parameters: stage, proliferation (Ki67), apoptosis (in situ DNA nick end labeling), the anti-apoptotic protein Bcl-2, tumor suppressors p53 and retinoblastoma protein (Rb), the Rb-related protein p130, cyclin E, and the cyclin-dependent kinase inhibitor p27. The protein expression in each tumor was reported as the percentage of positively staining cells. RESULTS: The analysis focused on Stage 1 to 3 tumors. Analysis found that p53 expression increased progressively with stage, and Rb and p27 decreased with increasing stage. Overall, the cyclin E levels correlated with the proliferative index. Cyclin E levels were low in Stage 1 tumors and elevated in Stage 2 tumors, but were decreased in Stage 3 tumors. Multivariate analysis uncovered a correlation between cyclin E and proliferation (Ki67) and a weak correlation between p53 and Bcl-2 and between p27 and Rb. A strong correlation was found between the expression of p53 and p130, which was apparent in Stages 1 and 3, but not in Stage 2. Furthermore, high levels of p130 protein were detected primarily in the cytoplasm. CONCLUSIONS: These results suggest a novel p53/p130 axis in bladder tumors.


Assuntos
Carcinoma de Células de Transição/patologia , Proteínas de Neoplasias/fisiologia , Proteína p130 Retinoblastoma-Like/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Carcinoma de Células de Transição/química , Divisão Celular , Núcleo Celular/química , Ciclina E/análise , Inibidor de Quinase Dependente de Ciclina p27/análise , Citoplasma/química , Feminino , Humanos , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteína p130 Retinoblastoma-Like/análise , Neoplasias da Bexiga Urinária/química
6.
J Virol ; 80(16): 8236-47, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16873279

RESUMO

Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Imunidade Celular/genética , Mucosa Intestinal/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infecções por HIV/imunologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Regulação para Cima , Replicação Viral
7.
J Virol ; 79(5): 2709-19, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15708990

RESUMO

Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections lead to rapid depletion of CD4(+) T cells from gut-associated lymphoid tissue (GALT). Although the administration of antiretroviral therapy (ART) has been shown to increase CD4(+) T-cell levels in the peripheral blood in both SIV and HIV infections, its efficacy in restoring intestinal mucosal CD4(+) T cells has not been well investigated. To gain insights into the molecular mechanisms of virally induced disruptions in the mucosal immune system, we have evaluated longitudinal changes in viral burden, T-cell subsets, and mucosal gene expression profiles in SIV-infected rhesus macaques in the absence or presence of ART. Our results demonstrate a dramatic suppression of mucosal viral loads and rapid reconstitution of CD4(+) T cells in GALT in animals receiving ART that were not observed in untreated SIV-infected animals. DNA microarray-based gene expression profiling indicated that CD4(+) T-cell restoration in GALT was associated with up regulation of growth factors and genes involved in repair and regeneration of the mucosal epithelium. In contrast, untreated SIV-infected animals increased expression of lymphocyte activation and inflammatory response-associated genes and did not up regulate mucosal growth and repair associated transcription. In conclusion, these data indicate that initiating ART in primary SIV infection may lead to the restoration of the mucosal immune system through reduction of inflammation and promotion of epithelial repair in the intestinal mucosa.


Assuntos
Adenina/análogos & derivados , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Adenina/uso terapêutico , Animais , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/genética , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Imunidade nas Mucosas/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/fisiopatologia , Mucosa Intestinal/virologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/imunologia , Tecido Linfoide/fisiopatologia , Tecido Linfoide/virologia , Macaca mulatta , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Organofosfonatos/uso terapêutico , Regeneração/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Vírus da Imunodeficiência Símia/isolamento & purificação , Tenofovir
8.
Proc Natl Acad Sci U S A ; 102(28): 9860-5, 2005 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-15980151

RESUMO

Limited information is available on the molecular mechanisms by which long-term HIV-1-infected nonprogressors suppress HIV-1 infection and maintain immune functions. The intestinal mucosal immune system is an early target for HIV-1 infection and severe CD4+ T cell depletion. We evaluated mucosal T lymphocyte subsets, virus-specific cellular responses, gene expression profiles, and viral loads in intestinal mucosal biopsies of long-term nonprogressor (LTNP) patients as compared to chronically HIV-1-infected patients with high viral loads (HVLs) and CD4+ T cell loss, as well as HIV-seronegative healthy individuals. This study aims to identify the mucosal correlates of HIV disease progression and to determine the molecular changes associated with immune and intestinal dysfunction. LTNP patients had undetectable viral loads, normal CD4+ T cell levels, and virus-specific cellular responses in peripheral blood and mucosal compartments. Microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of HVL patients as compared to LTNP patients. Genes associated with cell cycle regulation, lipid metabolism, and epithelial cell barrier and digestive functions were down-regulated in both HVL and LTNP patients. This may adversely influence nutrient adsorption and digestive functions, with the potential to impact the efficacy of antiretroviral therapy. We demonstrate that the maintenance of mucosal T cells, virus-specific responses, and distinct gene expression profiles correlate with clinical outcome in LTNP patients. However, the intestinal mucosal immune system remains an important target of HIV-1 infection in LTNP, and these effects may ultimately contribute toward disease progression.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Regulação da Expressão Gênica , Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , HIV-1/imunologia , Imunidade Celular/imunologia , Mucosa Intestinal/imunologia , Progressão da Doença , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Carga Viral
9.
Dig Dis Sci ; 48(6): 1073-80, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12822865

RESUMO

In vitro studies suggest that H. pylori induces apoptosis in gastric epithelial cells and perhaps in gastric lymphocytes as well. However, the early effects of H. pylori infection on lymphocyte apoptosis have not been examined in experimental animal models, nor have studies been performed using markers specific for T cells and T-cell subsets. Gastric T-cell apoptosis and Fas ligand expression were examined by flow cytometry after experimental infection of rhesus macaques with H. pylori. Infection induced transient apoptosis of gastric CD4+ and CD8+ T-cells, which began as soon as three days after inoculation and declined to baseline within eight weeks. Fas ligand expression showed a similar transient induction, suggesting that it mediates gastric T-cell apoptosis. We propose that transient, Fas-mediated apoptosis in gastric lymphocytes is a compensatory response to the initial T-cell inflammatory response after acute H. pylori infection.


Assuntos
Apoptose , Infecções por Helicobacter/patologia , Helicobacter pylori , Linfócitos T/patologia , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Helicobacter pylori/imunologia , Imunoglobulina G/imunologia , Macaca mulatta , Masculino , Estômago/patologia , Receptor fas/metabolismo
10.
J Virol ; 77(21): 11708-17, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14557656

RESUMO

Gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body and is an important target for human immunodeficiency virus type 1 (HIV-1). We analyzed longitudinal jejunal biopsy samples from HIV-1-infected patients, during both primary and chronic stages of HIV-1 infection, prior to and following the initiation of highly active antiretroviral therapy (HAART) to determine the onset of CD4(+) T-cell depletion and the effect of HAART on the restoration of CD4(+) T cells in GALT. Severe depletion of intestinal CD4(+) T cells occurred during primary HIV-1 infection. Our results showed that the restoration of intestinal CD4(+) T cells following HAART in chronically HIV-1-infected patients was substantially delayed and incomplete. In contrast, initiation of HAART during early stages of infection resulted in near-complete restoration of intestinal CD4(+) T cells, despite the delay in comparison to peripheral blood CD4(+) T-cell recovery. DNA microarray analysis of gene expression profiles and flow-cytometric analysis of lymphocyte homing and cell proliferation markers demonstrated that cell trafficking to GALT and not local proliferation contributed to CD4(+) T-cell restoration. Evaluation of jejunal biopsy samples from long-term HIV-1-infected nonprogressors showed maintenance of normal CD4(+) T-cell levels in both GALT and peripheral blood. Our results demonstrate that near-complete restoration of mucosal immune system can be achieved by initiating HAART early in HIV-1 infection. Monitoring of the restoration and/or maintenance of CD4(+) T cells in GALT provides a more accurate assessment of the efficacy of antiviral host immune responses as well as HAART.


Assuntos
Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/patologia , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Jejuno/imunologia , Tecido Linfoide/imunologia , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular , Doença Crônica , Feminino , Citometria de Fluxo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Imuno-Histoquímica , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
11.
Virology ; 312(1): 84-94, 2003 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-12890623

RESUMO

During primary simian immunodeficiency virus (SIV) infection, CD4+ T cells are severely depleted in gut-associated lymphoid tissue (GALT), while CD8+ T-cell numbers dramatically increase. To gain an understanding of the molecular basis of this disruption in T-cell homeostasis, host gene expression was monitored in longitudinal jejunum tissue biopsies from SIV-infected rhesus macaques by DNA microarray analysis. Transcription of cyclin E1, CDC2, retinoblastoma, transforming growth factor (TGF), fibroblast growth factor (FGF), and interleukin-2 was repressed while cyclins B1 and D2 and transcription factor E2F were upregulated, indicating a complex dysregulation of growth and proliferation within the intestinal mucosa. Innate, cell-mediated, and humoral immune responses were markedly upregulated in animals that significantly reduced their viral loads and retained more intestinal CD4+ T cells. We conclude that the alterations in intestinal gene expression during primary SIV infection were characteristic of a broad-range immune response, and reflective of the efficacy of viral suppression.


Assuntos
Ciclo Celular/genética , Perfilação da Expressão Gênica , Substâncias de Crescimento/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Vírus da Imunodeficiência Símia/fisiologia , Animais , Apresentação de Antígeno , Análise por Conglomerados , Regulação da Expressão Gênica , Mucosa Intestinal/imunologia , Macaca mulatta , Masculino , RNA/análise , RNA/genética , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Estresse Fisiológico/genética , Linfócitos T/imunologia , Transcrição Gênica , Viremia/genética
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