Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Virology ; 559: 165-172, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33930819

RESUMO

SARS coronavirus 1 (SARS-CoV-1) causes a respiratory infection that can lead to acute respiratory distress characterized by inflammation and high levels of cytokines in the lung tissue. In this study we constructed a herpes simplex virus 1 replication-defective mutant vector expressing SARS-CoV-1 spike protein as a potential vaccine vector and to probe the effects of spike protein on host cells. The spike protein expressed from this vector is functional in that it localizes to the surface of infected cells and induces fusion of ACE2-expressing cells. In immunized mice, the recombinant vector induced antibodies that bind to spike protein in an ELISA assay and that show neutralizing activity. The spike protein expressed from this vector can induce the expression of cytokines in an ACE2-independent, MyD88-dependent process. These results argue that the SARS-CoV-1 spike protein intrinsically activates signaling pathways that induce cytokines and contribute directly to the inflammatory process of SARS.


Assuntos
Anticorpos Neutralizantes/imunologia , Herpesvirus Humano 1/genética , Imunidade Inata , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Fusão Celular , Linhagem Celular , Citocinas/imunologia , Vetores Genéticos , Humanos , Camundongos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas Virais/imunologia
2.
J Virol ; 93(20)2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31375576

RESUMO

BLT (bone marrow-liver-thymus) humanized mice, which reconstitute a functional human immune system, develop prototypic human virus-specific CD8+ T cell responses following infection with human immunodeficiency virus type 1 (HIV-1). We explored the utility of the BLT model for HIV-1 vaccine development by immunizing BLT mice against the conserved viral Gag protein, utilizing a rapid prime-boost protocol of poly(lactic-co-glycolic) acid microparticles and a replication-defective herpes simplex virus (HSV) recombinant vector. After HIV-1 challenge, the mice developed broad, proteome-wide gamma interferon-positive (IFN-γ+) T cell responses against HIV-1 that reached magnitudes equivalent to what is observed in HIV-1-infected individuals. The functionality of these responses was underscored by the consistent emergence of escape mutations in multiple CD8+ T cell epitopes during the course of infection. Although prechallenge vaccine-induced responses were largely undetectable, the Gag immunization increased both the magnitude and the kinetics of anamnestic Gag-specific T cell responses following HIV-1 infection, and the magnitude of these postchallenge Gag-specific responses was inversely correlated with acute HIV-1 viremia. Indeed, Gag immunization was associated with a modest but significant 0.5-log reduction in HIV-1 viral load when analyzed across four experimental groups of BLT mice. Notably, the HSV vector induced elevated plasma concentrations of polarizing cytokines and chemotactic factors, including interleukin-12p70 (IL-12p70) and MIP-1α, which were positively correlated with the magnitude of Gag-specific responses. Overall, these results support the ability of BLT mice to recapitulate human pathogen-specific T cell responses and to respond to immunization; however, additional improvements to the model are required to develop a robust system for testing HIV-1 vaccine efficacy.IMPORTANCE Advances in the development of humanized mice have raised the possibility of a small-animal model for preclinical testing of an HIV-1 vaccine. Here, we describe the capacity of BLT humanized mice to mount broadly directed HIV-1-specific human T cell responses that are functionally active, as indicated by the rapid emergence of viral escape mutations. Although immunization of BLT mice with the conserved viral Gag protein did not result in detectable prechallenge responses, it did increase the magnitude and kinetics of postchallenge Gag-specific T cell responses, which was associated with a modest but significant reduction in acute HIV-1 viremia. Additionally, the BLT model revealed immunization-associated increases in the plasma concentrations of immunomodulatory cytokines and chemokines that correlated with more robust T cell responses. These data support the potential utility of the BLT humanized mouse for HIV-1 vaccine development but suggest that additional improvements to the model are warranted.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Linfócitos T/imunologia , Linfócitos T/virologia , Viremia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Doença Aguda , Animais , Evolução Biológica , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunização , Camundongos , Camundongos Transgênicos , Linfócitos T/metabolismo , Carga Viral
3.
Nat Commun ; 6: 7562, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-26108174

RESUMO

Initial events after exposure determine HIV-1 disease progression, underscoring a critical need to understand host mechanisms that interfere with initial viral replication. Although associated with chronic HIV-1 control, it is not known whether interleukin-21 (IL-21) contributes to early HIV-1 immunity. Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells. IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling. Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression. Together, these findings reveal a novel antiviral IL-21-miR-29 axis that promotes CD4 T-cell-intrinsic resistance to HIV-1 infection, and suggest a role for IL-21 in initial HIV-1 control in vivo.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/metabolismo , HIV-1/fisiologia , Interleucinas/farmacologia , MicroRNAs/metabolismo , Animais , Anticorpos Monoclonais Humanizados , Humanos , Camundongos , Camundongos Knockout , MicroRNAs/genética , Baço/citologia , Técnicas de Cultura de Tecidos
4.
PLoS One ; 8(10): e77780, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24204962

RESUMO

An estimated 34 million people are living with HIV worldwide (UNAIDS, 2012), with the number of infected persons rising every year. Increases in HIV prevalence have resulted not only from new infections, but also from increases in the survival of HIV-infected persons produced by effective anti-retroviral therapies. Augmentation of anti-viral immune responses may be able to further increase the survival of HIV-infected persons. One strategy to augment these responses is to reinvigorate exhausted anti-HIV immune cells present in chronically infected persons. The PD-1-PD-L1 pathway has been implicated in the exhaustion of virus-specific T cells during chronic HIV infection. Inhibition of PD-1 signaling using blocking anti-PD-1 antibodies has been shown to reduce simian immunodeficiency virus (SIV) loads in monkeys. We now show that PD-1 blockade can improve control of HIV replication in vivo in an animal model. BLT (Bone marrow-Liver-Thymus) humanized mice chronically infected with HIV-1 were treated with an anti-PD-1 antibody over a 10-day period. The PD-1 blockade resulted in a very significant 45-fold reduction in HIV viral loads in humanized mice with high CD8(+) T cell expression of PD-1, compared to controls at 4 weeks post-treatment. The anti-PD-1 antibody treatment also resulted in a significant increase in CD8(+) T cells. PD-1 blockade did not affect T cell expression of other inhibitory receptors co-expressed with PD-1, including CD244, CD160 and LAG-3, and did not appear to affect virus-specific humoral immune responses. These data demonstrate that inhibiting PD-1 signaling can reduce HIV viral loads in vivo in the humanized BLT mouse model, suggesting that blockade of the PD-1-PD-L1 pathway may have therapeutic potential in the treatment of patients already infected with the AIDS virus.


Assuntos
Anticorpos Bloqueadores/farmacologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carga Viral/efeitos dos fármacos , Animais , Western Blotting , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Receptor de Morte Celular Programada 1/imunologia
5.
J Infect Dis ; 208 Suppl 2: S150-4, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24151322

RESUMO

CD8(+) T-cell responses play a critical role in the control of human immunodeficiency virus (HIV) infection, and recent vaccine studies in nonhuman primates now demonstrate the ability of T cells to prevent the early dissemination of simian immunodeficiency virus and perhaps clear residual infection. Recent advances in humanized mouse models, in particular the humanized bone marrow-liver-thymus (BLT) mouse model, show promise in their ability not only to support sustained infection with HIV, but also to recapitulate human HIV-specific immunity. The availability of a small-animal model with which to study human-specific immune responses to HIV would greatly facilitate the elucidation of mechanisms of immune control, as well as accelerate the iterative testing of promising vaccine candidates. Here we discuss data from our recent study detailing the composition and efficacy of HIV-specific CD8(+) T-cell responses in humanized BLT mice that was recently presented at a Harvard Center for AIDS Research symposium on humanized mouse models for HIV vaccine design.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Infecções por HIV/imunologia , Infecções por HIV/patologia , HIV-1/imunologia , HIV-1/patogenicidade , Animais , Humanos , Camundongos , Camundongos SCID
6.
Sci Transl Med ; 4(143): 143ra98, 2012 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-22814851

RESUMO

The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV-1 as a model pathogen and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8(+) T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8(+) T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens.


Assuntos
Linfócitos T CD8-Positivos/imunologia , HIV-1/imunologia , Animais , Infecções por HIV/imunologia , Antígenos HLA-B/metabolismo , Humanos , Imunidade Celular/imunologia , Camundongos
7.
J Infect Dis ; 203(10): 1434-41, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21498376

RESUMO

BACKGROUND: Genital infection with herpes simplex virus 2 (HSV-2) is linked to an increased risk of infection with human immunodeficiency virus (HIV) in areas such as Sub-Saharan Africa. Thus, an effective genital herpes vaccine would be an important weapon in the fight against HIV/AIDS. METHODS: To test whether a current vaccine candidate can protect against HSV-2 from Sub-Saharan Africa, we examined the ability of an HSV-2 vaccine strain, dl5-29, and other HSV-2 replication-defective mutant strains to protect against genital challenge with US or South African strains in a murine model. RESULTS: Immunization with dl5-29 reduces infection by both viruses but is significantly more efficacious against the US virus than against the African virus. Furthermore, another US vaccine strain was more efficacious against US than against African viruses, and the converse was observed for the parallel African vaccine strain. Nevertheless, protection against the African viruses was significantly less with all vaccines used in this study. CONCLUSIONS: We conclude that there may be differences in protective epitopes and pathogenesis between the US and African strains that raise the need for increased doses of the existing vaccine candidate or an HSV-2 vaccine strain based on viruses from that region.


Assuntos
Herpes Genital/epidemiologia , Herpes Genital/virologia , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 2/patogenicidade , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Chlorocebus aethiops , Epitopos/imunologia , Feminino , Herpes Genital/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , África do Sul/epidemiologia , Estados Unidos/epidemiologia , Células Vero , Virulência
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...