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1.
Viruses ; 5(10): 2384-409, 2013 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-24084235

RESUMO

West Nile encephalitis emerged in 1999 in the United States, then rapidly spread through the North American continent causing severe disease in human and horses. Since then, outbreaks appeared in Europe, and in 2012, the United States experienced a new severe outbreak reporting a total of 5,387 cases of West Nile virus (WNV) disease in humans, including 243 deaths. So far, no human vaccine is available to control new WNV outbreaks and to avoid worldwide spreading. In this review, we discuss the state-of-the-art of West Nile vaccine development and the potential of a novel safe and effective approach based on recombinant live attenuated measles virus (MV) vaccine. MV vaccine is a live attenuated negative-stranded RNA virus proven as one of the safest, most stable and effective human vaccines. We previously described a vector derived from the Schwarz MV vaccine strain that stably expresses antigens from emerging arboviruses, such as dengue, West Nile or chikungunya viruses, and is strongly immunogenic in animal models, even in the presence of MV pre-existing immunity. A single administration of a recombinant MV vaccine expressing the secreted form of WNV envelope glycoprotein elicited protective immunity in mice and non-human primates as early as two weeks after immunization, indicating its potential as a human vaccine.


Assuntos
Febre do Nilo Ocidental/epidemiologia , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/isolamento & purificação , Animais , Modelos Animais de Doenças , Surtos de Doenças , Descoberta de Drogas/tendências , Europa (Continente)/epidemiologia , Humanos , Camundongos , América do Norte/epidemiologia , Primatas , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/isolamento & purificação , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/isolamento & purificação , Vacinas contra o Vírus do Nilo Ocidental/efeitos adversos
2.
Vaccine ; 31(36): 3718-25, 2013 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-23742993

RESUMO

Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, recently reemerged in the Indian Ocean, India and Southeast Asia, causing millions of cases of severe polyarthralgia. No specific treatment to prevent disease or vaccine to limit epidemics is currently available. Here we describe a recombinant live-attenuated measles vaccine (MV) expressing CHIKV virus-like particles comprising capsid and envelope structural proteins from the recent CHIKV strain La Reunion. Immunization of mice susceptible to measles virus induced high titers of CHIKV antibodies that neutralized several primary isolates. Specific cellular immune responses were also elicited. A single immunization with this vaccine candidate protected all mice from a lethal CHIKV challenge, and passive transfer of immune sera conferred protection to naïve mice. Measles vaccine is one of the safest and most effective human vaccines. A recombinant MV-CHIKV virus could make a safe and effective vaccine against chikungunya that deserves to be further tested in human trials.


Assuntos
Infecções por Alphavirus/prevenção & controle , Vírus Chikungunya/imunologia , Vacina contra Sarampo/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Proteínas do Capsídeo/imunologia , Febre de Chikungunya , Chlorocebus aethiops , Reações Cruzadas , Soros Imunes/imunologia , Imunidade Celular , Imunização Passiva , Camundongos , Camundongos Transgênicos , Vacinas Atenuadas/imunologia , Células Vero , Proteínas do Envelope Viral/imunologia
3.
J Infect Dis ; 206(2): 212-9, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22551814

RESUMO

West Nile virus (WNV) is a mosquito-borne flavivirus that emerged in North America and caused numerous cases of human encephalitis, thus urging the development of a vaccine. We previously demonstrated the efficacy of a recombinant measles vaccine (MV) expressing the secreted form of the envelope glycoprotein from WNV to prevent WNV encephalitis in mice. In the present study, we investigated the capacity of this vaccine candidate to control WNV infection in a primate model. We first established experimental WNV infection of squirrel monkeys (Saimiri sciureus). A high titer of virus was detected in plasma on day 2 after infection, and viremia persisted for 5 days. A single immunization of recombinant MV-WNV vaccine elicited anti-WNV neutralizing antibodies that strongly reduced WNV viremia at challenge. This study demonstrates for the first time the capacity of a recombinant live attenuated measles vector to protect nonhuman primates from a heterologous infectious challenge.


Assuntos
Vacina contra Sarampo/imunologia , Proteínas do Envelope Viral/imunologia , Febre do Nilo Ocidental/prevenção & controle , Vírus do Nilo Ocidental/imunologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Saimiri , Proteínas do Envelope Viral/metabolismo
4.
Vaccine ; 28(41): 6730-9, 2010 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-20688034

RESUMO

Dengue disease is an increasing global health problem that threatens one-third of the world's population. To control this emerging arbovirus, an efficient preventive vaccine is still needed. Because four serotypes of dengue virus (DV) coexist and antibody-dependent enhanced infection may occur, most strategies developed so far rely on the administration of tetravalent formulations of four live attenuated or chimeric viruses. Here, we evaluated a new strategy based on the expression of a single minimal tetravalent DV antigen by a single replicating viral vector derived from pediatric live-attenuated measles vaccine (MV). We generated a recombinant MV vector expressing a DV construct composed of the four envelope domain III (EDIII) from the four DV serotypes fused with the ectodomain of the membrane protein (ectoM). After two injections in mice susceptible to MV infection, the recombinant vector induced neutralizing antibodies against the four serotypes of dengue virus. When immunized mice were further inoculated with live DV from each serotype, a strong memory neutralizing response was raised against all four serotypes. A combined measles-dengue vaccine might be attractive to immunize infants against both diseases where they co-exist.


Assuntos
Anticorpos Neutralizantes/sangue , Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Vacina contra Sarampo/imunologia , Proteínas do Envelope Viral/imunologia , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Chlorocebus aethiops , Dengue/imunologia , Vírus da Dengue/imunologia , Drosophila/citologia , Escherichia coli/metabolismo , Vetores Genéticos , Imunidade Humoral , Memória Imunológica , Masculino , Camundongos , Camundongos Transgênicos , Testes de Neutralização , Plasmídeos , Proteínas Recombinantes/imunologia , Células Vero
5.
J Virol ; 84(10): 5314-28, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20219934

RESUMO

Poxvirus-based human immunodeficiency virus (HIV) vaccine candidates are currently under evaluation in preclinical and clinical trials. Modified vaccinia virus Ankara (MVA) vectors have excellent safety and immunogenicity records, but their behavior in human cell cultures remains only partly characterized. We studied here various virological and immunological aspects of the interactions of MVA-HIV, a vaccine candidate developed by the French National Agency for AIDS Research (ANRS), with primary human cells. We report that MVA-HIV infects and drives Gag expression in primary macrophages, dendritic cells (DCs), and epithelial and muscle cells. MVA-HIV-infected DCs matured, efficiently presented Gag, Pol, and Nef antigens, and activated HIV-specific cytotoxic T lymphocytes (CTLs). As expected with this type of vector, infection was cytopathic and led to DC apoptosis. Coculture of MVA-HIV-infected epithelial cells or myotubes with DCs promoted efficient Gag antigen major histocompatibility complex class I (MHC-I) cross-presentation without inducing direct infection and death of DCs. Antigen-presenting cells (APCs) infected with MVA-HIV also activated HIV-specific CD4(+) T cells. Moreover, exposure of DCs to MVA-HIV or to MVA-HIV-infected myotubes induced type I interferon (IFN) production and inhibited subsequent HIV replication and transfer to lymphocytes. Altogether, these results show that MVA-HIV promotes efficient MHC-I and MHC-II presentation of HIV antigens by APCs without facilitating HIV replication. Deciphering the immune responses to MVA in culture experiments will help in the design of innovative vaccine strategies.


Assuntos
Vacinas contra a AIDS/imunologia , Apresentação do Antígeno , Vetores Genéticos , Vírus Vaccinia/genética , Vacinas contra a AIDS/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Humanos , Linfócitos T Citotóxicos/imunologia
6.
J Exp Med ; 207(1): 39-49, 2010 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-20038599

RESUMO

The cytidine deaminase APOBEC3G (A3G) enzyme exerts an intrinsic anti-human immunodeficiency virus (HIV) defense by introducing lethal G-to-A hypermutations in the viral genome. The HIV-1 viral infectivity factor (Vif) protein triggers degradation of A3G and counteracts this antiviral effect. The impact of A3G on the adaptive cellular immune response has not been characterized. We examined whether A3G-edited defective viruses, which are known to express truncated or misfolded viral proteins, activate HIV-1-specific (HS) CD8+ cytotoxic T lymphocytes (CTLs). To this end, we compared the immunogenicity of cells infected with wild-type or Vif-deleted viruses in the presence or absence of the cytidine deaminase. The inhibitory effect of A3G on HIV replication was associated with a strong activation of cocultivated HS-CTLs. CTL activation was particularly marked with Vif-deleted HIV and with viruses harboring A3G. Enzymatically inactive A3G mutants failed to enhance CTL activation. We also engineered proviruses bearing premature stop codons in their genome as scars of A3G editing. These viruses were not infectious but potently activated HS-CTLs. Therefore, the pool of defective viruses generated by A3G represents an underestimated source of viral antigens. Our results reveal a novel function for A3G, acting not only as an intrinsic antiviral factor but also as an inducer of the adaptive immune system.


Assuntos
Imunidade Adaptativa , Linfócitos T CD8-Positivos/imunologia , Citidina Desaminase/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Ativação Linfocitária/imunologia , Desaminase APOBEC-3G , Animais , Antígenos Virais/genética , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Códon de Terminação/genética , Códon de Terminação/imunologia , Códon de Terminação/metabolismo , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Deleção de Genes , Genes vif/genética , Genes vif/imunologia , Infecções por HIV/enzimologia , Infecções por HIV/genética , HIV-1/genética , HIV-1/metabolismo , Humanos , Ativação Linfocitária/genética , Camundongos , Camundongos Transgênicos , Mutação , Provírus/genética , Provírus/imunologia , Provírus/metabolismo , Edição de RNA/genética , Edição de RNA/imunologia , RNA Viral/genética , RNA Viral/imunologia , RNA Viral/metabolismo , Replicação Viral/genética , Replicação Viral/imunologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Produtos do Gene vif do Vírus da Imunodeficiência Humana/imunologia
7.
Virology ; 388(1): 191-203, 2009 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-19345390

RESUMO

Although a live attenuated HIV vaccine is not currently considered for safety reasons, a strategy inducing both T cells and neutralizing antibodies to native assembled HIV-1 particles expressed by a replicating virus might mimic the advantageous characteristics of live attenuated vaccine. To this aim, we generated a live attenuated recombinant measles vaccine expressing HIV-1 Gag virus-like particles (VLPs) covered with gp160DeltaV1V2 Env protein. The measles-HIV virus replicated efficiently in cell culture and induced the intense budding of HIV particles covered with Env. In mice sensitive to MV infection, this recombinant vaccine stimulated high levels of cellular and humoral immunity to both MV and HIV with neutralizing activity. The measles-HIV virus infected human professional antigen-presenting cells, such as dendritic cells and B cells, and induced efficient presentation of HIV-1 epitopes and subsequent activation of human HIV-1 Gag-specific T cell clones. This candidate vaccine will be next tested in non-human primates. As a pediatric vaccine, it might protect children and adolescents simultaneously from measles and HIV.


Assuntos
Vacinas contra a AIDS/imunologia , Vacina contra Sarampo/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Animais , Antecipação Genética , Chlorocebus aethiops , Humanos , Vírus do Sarampo , Proteína Cofatora de Membrana/genética , Camundongos , Vacinas Sintéticas , Células Vero , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
8.
Cancer Res ; 68(12): 4882-92, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18559536

RESUMO

Despite conventional medical and surgical treatments, malignant pleural mesothelioma (MPM) remains incurable. Oncovirotherapy (i.e., the use of replication-competent virus for cancer treatment) is currently explored in clinical trials. In this study, we investigated the antineoplastic potential of a new oncolytic viral agent, a live-attenuated measles virus (MV) strain derived from the Edmonston vaccine lineage (Schwarz strain). We evaluated both oncolytic activity and immunoadjuvant properties of the MV vaccine strain on mesothelioma tumor cells. Infectivity, syncytium formation, and cytolytic activity of MV were studied on a panel of mesothelioma cells derived from pleural effusions of MPM patients. We observed that MV infected preferentially MPM cell lines in comparison with nontransformed mesothelial cells, leading to an efficient killing of a significant fraction of tumor cells. A cytoreductive activity was also evidenced through formation of multinuclear cellular aggregates (syncytia). The susceptibility of MPM cell lines to measles infection was assessed by the analysis of cell surface expression of the MV vaccine receptor (CD46). We also evaluated whether MV infection of mesothelioma cells could elicit an autologous antitumor immune response. We showed that MV Schwarz strain induced apoptotic cell death of infected mesothelioma cells, which were efficiently phagocytosed by dendritic cells (DC). Loading of DCs with MV-infected MPM cells induced DC spontaneous maturation, as evidenced by the increased expression of MHC and costimulatory molecules along with the production of proinflammatory cytokines. Priming of autologous T cells by DCs loaded with MV-infected MPM cells led to a significant proliferation of tumor-specific CD8 T cells. Altogether, these data strongly support the potential of oncolytic MV as an efficient therapeutic agent for mesothelioma cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Vírus do Sarampo/genética , Sarampo/imunologia , Mesotelioma/terapia , Mesotelioma/virologia , Terapia Viral Oncolítica , Derrame Pleural Maligno/imunologia , Animais , Apoptose , Chlorocebus aethiops , Apresentação Cruzada , Efeito Citopatogênico Viral , Células Dendríticas/patologia , Células Dendríticas/virologia , Humanos , Sarampo/patologia , Sarampo/virologia , Vírus do Sarampo/imunologia , Proteína Cofatora de Membrana/metabolismo , Mesotelioma/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Fagocitose , Derrame Pleural Maligno/patologia , Derrame Pleural Maligno/virologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Células Vero , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Comp Immunol Microbiol Infect Dis ; 31(2-3): 271-91, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17869338

RESUMO

The measles vaccine is one of the best vaccines currently available. Over the last 30 years, it has been administered to hundreds of millions of children and has proved to be both effective and safe. This attenuated live virus induces life-long immunity after only one or two injections. It is produced on a large scale, with ease, in many countries and is distributed at low cost. These excellent characteristics led us to consider its use as a pediatric live vector, to simultaneously immunize children or adolescents against measles and other viral infections, such as human immunodeficiency virus (HIV) or flavivirus infections. For this purpose, we have developed a vector derived from the live attenuated Schwarz strain of the measles virus (MV). We have demonstrated the capacity of this vector to strongly and stably express genes encoding proteins from HIV and to induce specific humoral and cellular immune responses in vivo. Importantly, we observed that, at least in animal models, the vector can bypass measles vaccine pre-existing immunity when two doses of recombinant vaccine are administered. Clinical trials are in progress to confirm this observation in immunized adults. We also produced MV vectors expressing proteins from West Nile virus and other flaviviruses, which in the case of West Nile virus, protected against experimental challenge. Recombinant live attenuated MV might be used as bivalent vaccination vector to mass immunize children and adolescents against both measles and flaviviral diseases such as Dengue or Japanese Encephalitis in the developing world.


Assuntos
Infecções por Flavivirus/prevenção & controle , Flavivirus/imunologia , Vetores Genéticos , Vacina contra Sarampo , Vírus do Sarampo/imunologia , Vacinas contra Dengue , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/virologia , HIV/imunologia , Humanos , Vacina contra Sarampo/normas , Vírus do Sarampo/genética , Plasmídeos , Vacinas Atenuadas/normas , Vacinas Sintéticas
10.
PLoS Negl Trop Dis ; 1(3): e96, 2007 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-18160988

RESUMO

Dengue disease is an increasing global health problem that threatens one-third of the world's population. Despite decades of efforts, no licensed vaccine against dengue is available. With the aim to develop an affordable vaccine that could be used in young populations living in tropical areas, we evaluated a new strategy based on the expression of a minimal dengue antigen by a vector derived from pediatric live-attenuated Schwarz measles vaccine (MV). As a proof-of-concept, we inserted into the MV vector a sequence encoding a minimal combined dengue antigen composed of the envelope domain III (EDIII) fused to the ectodomain of the membrane protein (ectoM) from DV serotype-1. Immunization of mice susceptible to MV resulted in a long-term production of DV1 serotype-specific neutralizing antibodies. The presence of ectoM was critical to the immunogenicity of inserted EDIII. The adjuvant capacity of ectoM correlated with its ability to promote the maturation of dendritic cells and the secretion of proinflammatory and antiviral cytokines and chemokines involved in adaptive immunity. The protective efficacy of this vaccine should be studied in non-human primates. A combined measles-dengue vaccine might provide a one-shot approach to immunize children against both diseases where they co-exist.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Antígenos Virais/imunologia , Vírus da Dengue/imunologia , Vacina contra Sarampo/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Antígenos Virais/genética , Sobrevivência Celular , Chlorocebus aethiops , Citocinas/imunologia , Células Dendríticas/imunologia , Dengue/imunologia , Dengue/prevenção & controle , Vírus da Dengue/genética , Citometria de Fluxo , Imunofluorescência , Humanos , Memória Imunológica , Vacina contra Sarampo/genética , Camundongos , Vacinas Atenuadas/imunologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Células Vero , Replicação Viral
11.
J Virol ; 81(20): 11526-31, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17670824

RESUMO

In this study, we investigated in a flavivirus model (tick-borne encephalitis virus) the mechanisms of fusion inhibition by monoclonal antibodies directed to the different domains of the fusion protein (E) and to different sites within each of the domains by using in vitro fusion assays. Our data indicate that, depending on the location of their binding sites, the monoclonal antibodies impaired early or late stages of the fusion process, by blocking the initial interaction with the target membrane or by interfering with the proper formation of the postfusion structure of E, respectively. These data provide new insights into the mechanisms of flavivirus fusion inhibition by antibodies and their possible contribution to virus neutralization.


Assuntos
Anticorpos Monoclonais/farmacologia , Flavivirus/patogenicidade , Fusão de Membrana/efeitos dos fármacos , Proteínas Virais de Fusão/antagonistas & inibidores , Antivirais , Epitopos , Proteínas Virais de Fusão/imunologia
12.
Am J Trop Med Hyg ; 72(1): 74-81, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15728870

RESUMO

ChimeriVax-dengue (DEN) viruses are live attenuated vaccine candidates. They are constructed by replacing the premembrane (prM) and envelope (E) genes of the yellow fever (YF) 17D virus vaccine with the corresponding genes from wild-type DEN viruses (serotypes 1-4) isolated from humans. In this study, the growth kinetics of ChimeriVax-DEN1-4 and parent viruses (wild-type DEN-1-4 and YF 17D) were assessed in human myeloid dendritic cells (DCs) and in three hepatic cell lines (HepG2, Huh7, and THLE-3). In DC, ChimeriVax-DEN-1-4 showed similar growth kinetics to their parent viruses, wild-type DEN virus (propagated in Vero cells), or YF 17D virus (peak titers ~3-4.5 log(10) plaque-forming units (PFU)/mL at 48-72 hours post-infection). Parent wild-type DEN-1-4 viruses derived from C6/36 mosquito cells did not show any growth at a multiplicity of infection of 0.1 in DCs, except for DEN-2 virus, which grew to a modest titer of 2.5 log(10) PFU/mL at 48 hours post-infection. ChimeriVax-DEN1-4 grew to significantly lower titers (2-5 log(10) PFU/mL) than YF 17D virus in hepatic cell lines THLE-3 and HepG2, but not in Huh7 cells. These experiments suggest that ChimeriVax-DEN1-4 viruses replicate similarly to YF-VAX in DCs, but at a lower level than YF 17D virus in hepatic cell lines. The lack of growth of chimeric viruses in human hepatic cells suggests that these viruses may be less hepatotropic than YF 17D virus vaccine in humans.


Assuntos
Aedes/virologia , Células Dendríticas/virologia , Vírus da Dengue/fisiologia , Hepatócitos/virologia , Animais , Linhagem Celular , DNA Viral/química , DNA Viral/genética , Vírus da Dengue/genética , Vírus da Dengue/imunologia , Insetos Vetores/virologia , Vacinas Atenuadas/genética , Vacinas Virais/imunologia , Replicação Viral , Vacinas contra o Vírus do Nilo Ocidental
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