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1.
J Immunol ; 207(5): 1239-1249, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389623

RESUMO

HIV-1 infection substantially increases the risk of developing tuberculosis (TB). Mechanisms such as defects in the Th1 response to Mycobacterium tuberculosis in HIV-infected persons have been widely reported. However, Th1-independent mechanisms also contribute to protection against TB. To identify a broader spectrum of defects in TB immunity during HIV infection, we examined IL-17A and IL-22 production in response to mycobacterial Ags in peripheral blood of persons with latent TB infection and HIV coinfection. Upon stimulating with mycobacterial Ags, we observed a distinct CD4+ Th lineage producing IL-22 in the absence of IL-17A and IFN-γ. Mycobacteria-specific Th22 cells were present at high frequencies in blood and contributed up to 50% to the CD4+ T cell response to mycobacteria, comparable in magnitude to the IFN-γ Th1 response (median 0.91% and 0.55%, respectively). Phenotypic characterization of Th22 cells revealed that their memory differentiation was similar to M. tuberculosis-specific Th1 cells (i.e., predominantly early differentiated CD45RO+CD27+ phenotype). Moreover, CCR6 and CXCR3 expression profiles of Th22 cells were similar to Th17 cells, whereas their CCR4 and CCR10 expression patterns displayed an intermediate phenotype between Th1 and Th17 cells. Strikingly, mycobacterial IL-22 responses were 3-fold lower in HIV-infected persons compared with uninfected persons, and the magnitude of responses correlated inversely with HIV viral load. These data provide important insights into mycobacteria-specific Th subsets in humans and suggest a potential role for IL-22 in protection against TB during HIV infection. Further studies are needed to fully elucidate the role of IL-22 in protective TB immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interleucinas/metabolismo , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Subpopulações de Linfócitos T/imunologia , Adulto , Células Cultivadas , Coinfecção , Feminino , Soropositividade para HIV , Humanos , Interleucina-17/metabolismo , Masculino , África do Sul , Carga Viral , Adulto Jovem
2.
Front Immunol ; 12: 707355, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276702

RESUMO

HIV-1 increases susceptibility to pulmonary infection and disease, suggesting pathogenesis in the lung. However, the lung immune environment during HIV infection remains poorly characterized. This study examined T cell activation and the cytokine milieu in paired bronchoalveolar lavage (BAL) and blood from 36 HIV-uninfected and 32 HIV-infected participants. Concentrations of 27 cytokines were measured by Luminex, and T cells were phenotyped by flow cytometry. Blood and BAL had distinct cytokine profiles (p=0.001). In plasma, concentrations of inflammatory cytokines like IFN-γ (p=0.004) and TNF-α (p=0.004) were elevated during HIV infection, as expected. Conversely, BAL cytokine concentrations were similar in HIV-infected and uninfected individuals, despite high BAL viral loads (VL; median 48,000 copies/ml epithelial lining fluid). HIV-infected individuals had greater numbers of T cells in BAL compared to uninfected individuals (p=0.007); and BAL VL positively associated with CD4+ and CD8+ T cell numbers (p=0.006 and p=0.0002, respectively) and CXCL10 concentrations (p=0.02). BAL T cells were highly activated in HIV-infected individuals, with nearly 2-3 fold greater frequencies of CD4+CD38+ (1.8-fold; p=0.007), CD4+CD38+HLA-DR+ (1.9-fold; p=0.0006), CD8+CD38+ (2.8-fold; p=0.0006), CD8+HLA-DR+ (2-fold; p=0.022) and CD8+CD38+HLA-DR+ (3.6-fold; p<0.0001) cells compared to HIV-uninfected individuals. Overall, this study demonstrates a clear disruption of the pulmonary immune environment during HIV infection, with readily detectable virus and activated T lymphocytes, which may be driven to accumulate by local chemokines.

3.
Front Immunol ; 9: 1995, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233588

RESUMO

Persistent antigen stimulation in chronic infections has been associated with antigen-specific T cell dysfunction and upregulation of inhibitory receptors, including programmed cell death protein 1 (PD-1). Pulmonary tuberculosis (TB) disease is characterized by high levels of Mycobacterium tuberculosis (Mtb), yet the relationship between bacterial load, PD-1 expression, and Mtb-specific T cell function in human TB has not been well-defined. Using peripheral blood samples from adults with LTBI and with pulmonary TB disease, we tested the hypothesis that PD-1 expression is associated with bacterial load and functional capacity of Mtb-specific T cell responses. We found that PD-1 was expressed at significantly higher levels on Th1 cytokine-producing Mtb-specific CD4 T cells from patients with smear-positive TB, compared with smear-negative TB and LTBI, which decreased after completion of anti-TB treatment. By contrast, expression of PD-1 on Mtb-specific CD8 T cells was significantly lower than on Mtb-specific CD4 T cells and did not differ by Mtb infection and disease status. In vitro stimulation of PBMC with Mtb antigens demonstrated that PD-1 is induced on proliferating Mtb-specific CD4 T cells and that Th1 cytokine production capacity is preferentially maintained within PD-1+ proliferating CD4 T cells, compared with proliferating Mtb-specific CD4 T cells that lack PD-1 expression. Together, these data indicate that expression of PD-1 on Mtb-specific CD4 T cells is indicative of mycobacterial antigen exposure and identifies a population of effector cells with Th1 cytokine production capacity. These studies provide novel insights into the role of the PD-1 pathway in regulating CD4 and CD8 T cell responses in Mtb infection and provide rationale for future studies to evaluate PD-1 expression on antigen-specific CD4 T cells as a potential biomarker for bacterial load and treatment response in human TB.


Assuntos
Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Receptor de Morte Celular Programada 1/metabolismo , Células Th1/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Antígenos de Bactérias/imunologia , Carga Bacteriana , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Adulto Jovem
4.
J Infect Dis ; 216(12): 1550-1560, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29029171

RESUMO

Human immunodeficiency virus type 1 (HIV) infection substantially increases the risk of developing tuberculosis. There is extensive depletion of Mycobacterium tuberculosis-specific CD4+ T cells in blood during early HIV infection, but little is known about responses in the lungs at this stage. Given that mucosal organs are a principal target for HIV-mediated CD4+ T-cell destruction, we investigated M. tuberculosis-specific responses in bronchoalveolar lavage (BAL) from persons with latent M. tuberculosis infection and untreated HIV coinfection with preserved CD4+ T-cell counts. M. tuberculosis-specific CD4+ T-cell cytokine (interferon γ, tumor necrosis factor α, and interleukin 2) responses were discordant in frequency and function between BAL and blood. Responses in BAL were 15-fold lower in HIV-infected persons as compared to uninfected persons (P = .048), whereas blood responses were 2-fold lower (P = .006). However, an increase in T cells in the airways in HIV-infected persons resulted in the overall number of M. tuberculosis-specific CD4+ T cells in BAL being similar. Our study highlights the important insights gained from studying M. tuberculosis immunity at the site of disease during HIV infection.


Assuntos
Sangue/imunologia , Linfócitos T CD4-Positivos/imunologia , Coinfecção/imunologia , Infecções por HIV/imunologia , Tuberculose Latente/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Adulto , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Infecções por HIV/complicações , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Tuberculose Latente/complicações , Masculino , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
5.
Tuberculosis (Edinb) ; 101: 25-30, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27865393

RESUMO

HIV-1 is recognized to increase the risk for tuberculosis even before CD4+ T cell deficiency is profound. To better understand how HIV-1 alters immunity to latent tuberculosis, we compared the magnitude and functional profile of mycobacteria-specific CD4+ T cells between HIV-uninfected and HIV-infected individuals, using flow cytometry. In HIV-1 infection, IFN-γ single positive mycobacteria-specific CD4+ T cells were decreased, while the frequency of polyfunctional cells (IFN-γ+IL-2+TNF-α+) remained unchanged. Moreover, the proportion of IFN-γ single positive cells correlated inversely with viral replication. Our results suggest that HIV-1 affects mycobacteria-specific cells differentially, depending on their functional capacity.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , HIV-1/isolamento & purificação , Interferon gama/sangue , Tuberculose Latente/imunologia , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Coleta de Amostras Sanguíneas/métodos , Contagem de Linfócito CD4 , Feminino , Citometria de Fluxo , Humanos , Tuberculose Latente/complicações , Masculino , Mycobacterium tuberculosis/imunologia , Carga Viral , Adulto Jovem
6.
J Gen Virol ; 95(Pt 10): 2267-2272, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24866849

RESUMO

Poxvirus vectors represent promising human immunodeficiency virus (HIV) vaccine candidates and were a component of the only successful HIV vaccine efficacy trial to date. We tested the immunogenicity of a novel recombinant capripoxvirus vector, lumpy skin disease virus (LSDV), in combination with modified vaccinia Ankara (MVA), both expressing genes from HIV-1. Here, we demonstrated that the combination regimen was immunogenic in rhesus macaques, inducing high-magnitude, broad and balanced CD4(+) and CD8(+) T-cell responses, and transient activation of the immune response. These studies support further development of LSDV as a vaccine vector.


Assuntos
Vacinas contra a AIDS/imunologia , Portadores de Fármacos , Vetores Genéticos , HIV-1/imunologia , Vírus da Doença Nodular Cutânea/genética , Vacinação/métodos , Vírus Vaccinia/genética , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Macaca mulatta , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
7.
Trends Microbiol ; 22(3): 107-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24581941

RESUMO

The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Síndrome de Imunodeficiência Adquirida/complicações , Micoses/tratamento farmacológico , Micoses/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antifúngicos/uso terapêutico , Humanos , Micoses/diagnóstico
8.
J Virol ; 87(9): 5151-60, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23449790

RESUMO

We previously reported that a recombinant pantothenate auxotroph of Mycobacterium bovis BCG expressing human immunodeficiency virus type 1 (HIV-1) subtype C Gag (rBCGpan-Gag) efficiently primes the mouse immune system for a boost with a recombinant modified vaccinia virus Ankara (rMVA) vaccine. In this study, we further evaluated the immunogenicity of rBCGpan-Gag in a nonhuman primate model. Two groups of chacma baboons were primed or mock primed twice with either rBCGpan-Gag or a control BCG. Both groups were boosted with HIV-1 Pr55(gag) virus-like particles (Gag VLPs). The magnitude and breadth of HIV-specific cellular responses were measured using a gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay, and the cytokine profiles and memory phenotypes of T cells were evaluated by polychromatic flow cytometry. Gag-specific responses were detected in all animals after the second inoculation with rBCGpan-Gag. Boosting with Gag VLPs significantly increased the magnitude and breadth of the responses in the baboons that were primed with rBCGpan-Gag. These responses targeted an average of 12 Gag peptides per animal, compared to an average of 3 peptides per animal for the mock-primed controls. Robust responses of Gag-specific polyfunctional T cells capable of simultaneously producing IFN-γ, tumor necrosis alpha (TNF-α), and interleukin-2 (IL-2) were detected in the rBCGpan-Gag-primed animals. Gag-specific memory T cells were skewed toward a central memory phenotype in both CD4(+) and CD8(+) T cell populations. These data show that the rBCGpan-Gag prime and Gag VLP boost vaccine regimen is highly immunogenic, inducing a broad and polyfunctional central memory T cell response. This report further indicates the feasibility of developing a BCG-based HIV vaccine that is safe for childhood HIV immunization.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Mycobacterium bovis/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/genética , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/genética , Humanos , Imunidade , Imunização Secundária , Interferon gama/genética , Interferon gama/imunologia , Mycobacterium bovis/genética , Papio ursinus , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Vacinação , Produtos do Gene gag do Vírus da Imunodeficiência Humana/administração & dosagem , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
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