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1.
Nature ; 543(7644): 248-251, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28151488

RESUMO

Zika virus (ZIKV) has recently emerged as a pandemic associated with severe neuropathology in newborns and adults. There are no ZIKV-specific treatments or preventatives. Therefore, the development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins. Here we demonstrate that a single low-dose intradermal immunization with lipid-nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope glycoproteins of a strain from the ZIKV outbreak in 2013 elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 µg of nucleoside-modified ZIKV mRNA-LNP protected mice against ZIKV challenges at 2 weeks or 5 months after vaccination, and a single dose of 50 µg was sufficient to protect non-human primates against a challenge at 5 weeks after vaccination. These data demonstrate that nucleoside-modified mRNA-LNP elicits rapid and durable protective immunity and therefore represents a new and promising vaccine candidate for the global fight against ZIKV.


Assuntos
RNA Mensageiro/administração & dosagem , RNA Mensageiro/química , Vacinas Virais/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Feminino , Glicoproteínas/genética , Glicoproteínas/imunologia , Injeções Intradérmicas , Macaca mulatta/imunologia , Macaca mulatta/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Estabilidade de RNA , RNA Mensageiro/genética , RNA Viral/administração & dosagem , RNA Viral/química , RNA Viral/genética , Fatores de Tempo , Vacinação , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem , Zika virus/química , Zika virus/genética , Infecção por Zika virus/imunologia
2.
Science ; 353(6303): 1045-1049, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27540005

RESUMO

HIV-1-specific broadly neutralizing antibodies (bNAbs) can protect rhesus monkeys against simian-human immunodeficiency virus (SHIV) challenge. However, the site of antibody interception of virus and the mechanism of antibody-mediated protection remain unclear. We administered a fully protective dose of the bNAb PGT121 to rhesus monkeys and challenged them intravaginally with SHIV-SF162P3. In PGT121-treated animals, we detected low levels of viral RNA and viral DNA in distal tissues for seven days following challenge. Viral RNA-positive tissues showed transcriptomic changes indicative of innate immune activation, and cells from these tissues initiated infection after adoptive transfer into naïve hosts. These data demonstrate that bNAb-mediated protection against a mucosal virus challenge can involve clearance of infectious virus in distal tissues.


Assuntos
Anticorpos Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/administração & dosagem , HIV-1/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/imunologia , Transferência Adotiva , Animais , Anticorpos Neutralizantes/imunologia , DNA Viral/análise , Feminino , Anticorpos Anti-HIV/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Macaca mulatta , RNA Viral/análise , Transcriptoma , Vagina/virologia
3.
J Neuroimmunol ; 295-296: 30-40, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27235346

RESUMO

We studied the effect of chronic morphine administration on the circulating dendritic cell population dynamics associated with SIV infection using rhesus macaques. Animals were either first infected with SIV and then given chronic morphine, or visa versa. SIV infection increased the numbers of myeloid DCs (mDCs), but morphine treatment attenuated this mDC expansion. In contrast, morphine increased the numbers of plasmacytoid DCs (pDCs) in SIV-infected animals. Finally, chronic morphine administration (no SIV) transiently increased the numbers of circulating pDCs. These results show that chronic morphine induces a significant alteration in the available circulating levels of critical antigen-presenting cells.


Assuntos
Células Dendríticas/efeitos dos fármacos , Infecções por HIV/patologia , Morfina/farmacologia , Entorpecentes/farmacologia , Análise de Variância , Animais , Contagem de Células , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Citometria de Fluxo , Infecções por HIV/veterinária , Macaca mulatta , Masculino , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Fatores de Tempo
4.
Cell ; 165(3): 656-67, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27085913

RESUMO

The earliest events following mucosal HIV-1 infection, prior to measurable viremia, remain poorly understood. Here, by detailed necropsy studies, we show that the virus can rapidly disseminate following mucosal SIV infection of rhesus monkeys and trigger components of the inflammasome, both at the site of inoculation and at early sites of distal virus spread. By 24 hr following inoculation, a proinflammatory signature that lacked antiviral restriction factors was observed in viral RNA-positive tissues. The early innate response included expression of NLRX1, which inhibits antiviral responses, and activation of the TGF-ß pathway, which negatively regulates adaptive immune responses. These data suggest a model in which the virus triggers specific host mechanisms that suppress the generation of antiviral innate and adaptive immune responses in the first few days of infection, thus facilitating its own replication. These findings have important implications for the development of vaccines and other strategies to prevent infection.


Assuntos
Inflamassomos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Animais , Medula Óssea/imunologia , Imunidade Inata , Imunidade nas Mucosas , Células Matadoras Naturais/imunologia , Macaca mulatta , Proteínas Mitocondriais/metabolismo , Monócitos/imunologia , Linfócitos T/imunologia , Transcriptoma , Fator de Crescimento Transformador beta/metabolismo , Replicação Viral
5.
J Immunol Res ; 2015: 673815, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26065003

RESUMO

Human and simian immunodeficiency virus (HIV and SIV) infections are characterized by manifestation of numerous opportunistic infections and inflammatory conditions in the oral mucosa. The loss of CD4(+) T cells that play a critical role in maintaining mucosal immunity likely contributes to this process. Here we show that CD4(+) T cells constitute a minor population of T cells in the oral mucosa and display a predominantly central memory phenotype mirroring other mucosal sites such as the rectal mucosa. Chronic SIV infection was associated with a near total depletion of CD4(+) T cells in the oral mucosa that appear to repopulate during antiretroviral therapy (ART). Repopulating CD4(+) T cells harbored a large fraction of Th17 cells suggesting that ART potentially reconstitutes oral mucosal immunity. However, a minor fraction of repopulating CD4(+) T cells harbored SIV DNA suggesting that the viral reservoir continues to persist in the oral mucosa during ART. Therapeutic approaches aimed at obtaining sustainable CD4(+) T cell repopulation in combination with strategies that can eradicate the latent viral reservoir in the oral mucosa are essential for better oral health and long-term outcome in HIV infected patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Mucosa Bucal/imunologia , Mucosa Bucal/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Terapia Antirretroviral de Alta Atividade/métodos , DNA Viral/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Imunidade nas Mucosas/imunologia , Memória Imunológica/imunologia , Mucosa Intestinal/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos
6.
Retrovirology ; 10: 71, 2013 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-23866829

RESUMO

BACKGROUND: HIV infection persists despite antiretroviral treatment (ART) and is reignited as soon as therapies are suspended. This vicious cycle is fueled by the persistence of viral reservoirs that are invulnerable to standard ART protocols, and thus therapeutic agents able to target these reservoirs are needed. One such agent, auranofin, has recently been shown to decrease the memory T-cell reservoir in chronically SIVmac251-infected macaques. Moreover, auranofin could synergize with a fully suppressive ART protocol and induce a drug-free post-therapy containment of viremia. RESULTS: We administered buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis currently in clinical trials for cancer, in combination with auranofin to chronically SIVmac251-infected macaques under highly-intensified ART (H-iART). The ART/auranofin/BSO therapeutic protocol was followed, after therapy suspension, by a significant decrease of viral RNA and DNA in peripheral blood as compared to pre-therapy levels. Drug-free post-therapy control of the infection was achieved in animals with pre-therapy viral loads ranging from values comparable to average human set points to levels largely higher. This control was dependent on the presence CD8+ cells and associated with enhanced levels of cell-mediated immune responses. CONCLUSIONS: The level of post-therapy viral set point reduction achieved in this study is the largest reported so far in chronically SIVmac251-infected macaques and may represent a promising strategy to improve over the current "ART for life" plight.


Assuntos
Antirretrovirais/administração & dosagem , Auranofina/administração & dosagem , Imunidade Celular , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Terapias em Estudo/métodos , Suspensão de Tratamento , Animais , Terapia Antirretroviral de Alta Atividade/métodos , Butionina Sulfoximina/administração & dosagem , DNA Viral/sangue , Macaca , RNA Viral/sangue , Vírus da Imunodeficiência Símia/isolamento & purificação , Resultado do Tratamento , Carga Viral
7.
AIDS ; 25(11): 1347-56, 2011 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-21505294

RESUMO

OBJECTIVES: A small pool of long-lived memory CD4 T cells harboring the retroviral genome is one main obstacle to HIV eradication. We tested the impact of the gold compound, auranofin, on phenotype and viability of CD4 T cells in vitro, and on persistence of lentiviral reservoir cells in vivo. DESIGN: In-vitro and in-vivo study. The pro-differentiating effect of auranofin was investigated in human primary CD4 T cells, and its capacity to deplete the viral DNA (vDNA) reservoir was tested in a pilot study involving six SIVmac251-infected macaques with viral loads stably suppressed by antiretroviral therapy (ART) (tenofovir/emtricitabine/raltegravir). The study was then amplified by intensifying ART using darunavir/r and including controls under intensified ART alone. All therapies were eventually suspended and viro-immunological parameters were monitored over time. METHODS: Cell subpopulations were quantitated by flow cytometry following proper hematological analyses. Viral load and cell-associated vDNA were quantitated by Taqman real-time PCR. RESULTS: In naïve, central memory and transitional memory CD4 T cells, auranofin induced both phenotype changes and cell death which were more pronounced in the memory compartment. In the pilot study in vivo, auranofin transiently decreased the cell-associated vDNA reservoir in peripheral blood. When ART was intensified, a sustained decrease in vDNA was observed only in auranofin-treated monkeys but not in controls treated with intensified ART alone. After therapy suspension, only monkeys that had received auranofin showed a deferred and subsequently blunted viral load rebound. CONCLUSION: These findings represent a first step towards a remission of primate lentiviral infections.


Assuntos
Antirretrovirais/farmacologia , Antirreumáticos/farmacologia , Auranofina/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Antirretrovirais/administração & dosagem , Antirreumáticos/administração & dosagem , Auranofina/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , DNA Viral/efeitos dos fármacos , Macaca mulatta , Projetos Piloto , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Resultado do Tratamento , Carga Viral , Latência Viral/imunologia , Replicação Viral/imunologia
8.
J Infect Dis ; 197(5): 693-7, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18266603

RESUMO

Candidate vaccine ChimeriVax viruses are attenuated, efficacious, safe, and highly unlikely to be transmitted by arthropod vectors. Nevertheless, concerns have been raised about the use of these vaccines because of the potential for recombination between vaccine and wild-type (WT) strains. To evaluate the vertebrate pathogenicity of such a worst-case recombinant, ChimeriVax-dengue (DEN) 4 virus was chimerized with the WT Asibi yellow fever virus. In this worst-case scenario, chimeric viruses remained fully attenuated in nonhuman primates. We therefore conclude that, even in the highly unlikely event of "virulent" backbone reversion, the safety of ChimeriVax-DEN vaccines would not be compromised.


Assuntos
Vírus da Dengue/patogenicidade , Vacinas Atenuadas/efeitos adversos , Vacinas contra o Vírus do Nilo Ocidental/administração & dosagem , Vacina contra Febre Amarela/administração & dosagem , Febre Amarela/imunologia , Vírus da Febre Amarela/patogenicidade , Animais , Quimera/genética , Quimera/virologia , Dengue/transmissão , Dengue/veterinária , Vírus da Dengue/imunologia , Modelos Animais de Doenças , Feminino , Macaca fascicularis/virologia , Masculino , Vacinas Atenuadas/genética , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Febre Amarela/genética , Febre Amarela/veterinária , Vacina contra Febre Amarela/genética
9.
J Leukoc Biol ; 80(5): 1175-82, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16923920

RESUMO

Highly active antiretroviral therapy (HAART) against human immunodeficiency virus type 1 (HIV-1) infection dramatically suppresses viral load, leading to marked reductions in HIV-1 associated morbidity and mortality. However, infected cell reservoirs and low-level replication persist in the face of suppressive HAART, leading invariably to viral rebound upon cessation of treatment. Toxins engineered to target the Env glycoprotein on the surface of productively infected cells represent a complementary strategy to deplete these reservoirs. We described previously highly selective killing of Env-expressing cell lines by CD4(178)-PE40 and 3B3(Fv)-PE38, recombinant derivatives of Pseudomonas aeruginosa exotoxin A containing distinct targeting moieties against gp120. In the present report, we compare the in vitro potency and breadth of these chimeric toxins against multiple clinical HIV-1 isolates, replicating in biologically relevant primary human target cell types. In PBMCs, 3B3(Fv)-PE38 blocked spreading infection by all isolates examined, with greater potency than CD4(178)-PE40. 3B3(Fv)-PE38 also potently inhibited spreading HIV-1 infection in primary macrophages. Control experiments demonstrated that in both target cell types, most of the 3B3(Fv)-PE38 activity was due to selective killing of infected cells, and not merely to neutralization by the antibody moiety of the chimeric toxin. High-dose treatment of rhesus macaques with 3B3(Fv)-PE38 did not induce liver toxicity, whereas equivalent dosage of CD4(178)-PE40 induced mild hepatotoxicity. These findings highlight the potential use of 3B3(Fv)-PE38 for depleting HIV-infected cell reservoirs persisting in the face of HAART.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV/efeitos dos fármacos , Imunotoxinas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Relação Dose-Resposta a Droga , Exotoxinas/administração & dosagem , Exotoxinas/efeitos adversos , Exotoxinas/farmacologia , HIV/isolamento & purificação , Humanos , Imunotoxinas/administração & dosagem , Imunotoxinas/efeitos adversos , Injeções Intravenosas , Leucócitos Mononucleares/virologia , Hepatopatias/patologia , Macaca , Macrófagos/virologia , Modelos Animais , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
10.
AIDS ; 19(1): 35-43, 2005 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-15627031

RESUMO

OBJECTIVE: To reconstitute immune responses capable of eliminating infected cells and suppressing viral load during chronic retroviral infection. DESIGN: : A topical, DNA-based therapeutic immunization (DermaVir) was designed to express most of the regulatory and structural viral genes in dendritic cells. METHODS: DermaVir alone and in combination with antiretroviral drugs was tested in chronically SIV-infected macaques. RESULTS: DermaVir provided virological, immunological and clinical benefit for SIV-infected macaques during chronic infection and AIDS. In combination with antiretroviral drugs, DermaVir augmented SIV-specific T-cell responses and enhanced control of viral load rebound during treatment interruptions. CONCLUSIONS: The results indicate the feasibility of therapeutic immunization even in immune compromised hosts, and suggest that DermaVir can complement antiretroviral drugs to sustain suppression of HIV-1 replication.


Assuntos
Vacinas contra a AIDS/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vacinas contra a AIDS/efeitos adversos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Animais , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Estudos de Coortes , Células Dendríticas/imunologia , Quimioterapia Combinada , Feminino , Imunização/métodos , Contagem de Linfócitos , Macaca , Masculino , RNA Viral/análise , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Suínos , Carga Viral/métodos , Replicação Viral/imunologia
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