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1.
Cell ; 177(5): 1124-1135.e16, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-31100267

RESUMEN

Vaccines to generate durable humoral immunity against antigenically evolving pathogens such as the influenza virus must elicit antibodies that recognize conserved epitopes. Analysis of single memory B cells from immunized human donors has led us to characterize a previously unrecognized epitope of influenza hemagglutinin (HA) that is immunogenic in humans and conserved among influenza subtypes. Structures show that an unrelated antibody from a participant in an experimental infection protocol recognized the epitope as well. IgGs specific for this antigenic determinant do not block viral infection in vitro, but passive administration to mice affords robust IgG subtype-dependent protection against influenza infection. The epitope, occluded in the pre-fusion form of HA, is at the contact surface between HA head domains; reversible molecular "breathing" of the HA trimer can expose the interface to antibody and B cells. Antigens that present this broadly immunogenic HA epitope may be good candidates for inclusion in "universal" flu vaccines.


Asunto(s)
Anticuerpos Antivirales/inmunología , Epítopos/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Inmunoglobulina G/inmunología , Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae , Adulto , Animales , Perros , Femenino , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Persona de Mediana Edad , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/prevención & control
2.
Immunity ; 48(1): 174-184.e9, 2018 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-29343437

RESUMEN

Human B cell antigen-receptor (BCR) repertoires reflect repeated exposures to evolving influenza viruses; new exposures update the previously generated B cell memory (Bmem) population. Despite structural similarity of hemagglutinins (HAs) from the two groups of influenza A viruses, cross-reacting antibodies (Abs) are uncommon. We analyzed Bmem compartments in three unrelated, adult donors and found frequent cross-group BCRs, both HA-head directed and non-head directed. Members of a clonal lineage from one donor had a BCR structure similar to that of a previously described Ab, encoded by different gene segments. Comparison showed that both Abs contacted the HA receptor-binding site through long heavy-chain third complementarity determining regions. Affinities of the clonal-lineage BCRs for historical influenza-virus HAs from both group 1 and group 2 viruses suggested that serial responses to seasonal influenza exposures had elicited the lineage and driven affinity maturation. We propose that appropriate immunization regimens might elicit a comparably broad response.


Asunto(s)
Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Virus de la Influenza A/inmunología , Adulto , Técnicas de Cultivo de Célula , Reacciones Cruzadas/inmunología , Femenino , Citometría de Flujo , Hemaglutininas Virales/inmunología , Humanos , Interferometría , Masculino
3.
Nature ; 543(7644): 248-251, 2017 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-28151488

RESUMEN

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.


Asunto(s)
ARN Mensajero/administración & dosificación , ARN Mensajero/química , Vacunas Virales/inmunología , Infección por el Virus Zika/prevención & control , Virus Zika/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/genética , Antígenos Virales/inmunología , Femenino , Glicoproteínas/genética , Glicoproteínas/inmunología , Inyecciones Intradérmicas , Macaca mulatta/inmunología , Macaca mulatta/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Nanopartículas/química , Estabilidad del ARN , ARN Mensajero/genética , ARN Viral/administración & dosificación , ARN Viral/química , ARN Viral/genética , Factores de Tiempo , Vacunación , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Vacunas Virales/administración & dosificación , Virus Zika/química , Virus Zika/genética , Infección por el Virus Zika/inmunología
4.
J Virol ; 90(1): 433-43, 2016 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-26491151

RESUMEN

UNLABELLED: Chikungunya virus (CHIKV) is an alphavirus responsible for causing epidemic outbreaks of polyarthralgia in humans. Because CHIKV is initially introduced via the skin, where γδ T cells are prevalent, we evaluated the response of these cells to CHIKV infection. CHIKV infection led to a significant increase in γδ T cells in the infected foot and draining lymph node that was associated with the production of proinflammatory cytokines and chemokines in C57BL/6J mice. γδ T cell(-/-) mice demonstrated exacerbated CHIKV disease characterized by less weight gain and greater foot swelling than occurred in wild-type mice, as well as a transient increase in monocytes and altered cytokine/chemokine expression in the foot. Histologically, γδ T cell(-/-) mice had increased inflammation-mediated oxidative damage in the ipsilateral foot and ankle joint compared to wild-type mice which was independent of differences in CHIKV replication. These results suggest that γδ T cells play a protective role in limiting the CHIKV-induced inflammatory response and subsequent tissue and joint damage. IMPORTANCE: Recent epidemics, including the 2004 to 2007 outbreak and the spread of CHIKV to naive populations in the Caribbean and Central and South America with resultant cases imported into the United States, have highlighted the capacity of CHIKV to cause explosive epidemics where the virus can spread to millions of people and rapidly move into new areas. These studies identified γδ T cells as important to both recruitment of key inflammatory cell populations and dampening the tissue injury due to oxidative stress. Given the importance of these cells in the early response to CHIKV, this information may inform the development of CHIKV vaccines and therapeutics.


Asunto(s)
Fiebre Chikungunya/inmunología , Virus Chikungunya/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/análisis , Linfocitos T/inmunología , Animales , Peso Corporal , Modelos Animales de Enfermedad , Miembro Posterior/patología , Histocitoquímica , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Linfocitos T/química
5.
Virol J ; 8: 376, 2011 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-21801412

RESUMEN

BACKGROUND: Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus that recently caused several large scale outbreaks/epidemics of arthritic disease in tropics of Africa, Indian Ocean basin and South-East Asia. This re-emergence event was facilitated by genetic adaptation (E1-A226V substitution) of CHIKV to a newly significant mosquito vector for this virus; Aedes albopictus. However, the molecular mechanism explaining the positive effect of the E1-A226V mutation on CHIKV fitness in this vector remains largely unknown. Previously we demonstrated that the E1-A226V substitution is also associated with attenuated CHIKV growth in cells depleted by cholesterol. METHODS: In this study, using a panel of CHIKV clones that varies in sensitivity to cholesterol, we investigated the possible relationship between cholesterol dependence and Ae. albopictus infectivity. RESULTS: We demonstrated that there is no clear mechanistic correlation between these two phenotypes. We also showed that the E1-A226V mutation increases the pH dependence of the CHIKV fusion reaction; however, subsequent genetic analysis failed to support an association between CHIKV dependency on lower pH, and mosquito infectivity phenotypes. CONCLUSION: the E1-A226V mutation probably acts at different steps of the CHIKV life cycle, affecting multiple functions of the virus.


Asunto(s)
Adaptación Biológica , Aedes/virología , Virus Chikungunya/fisiología , Colesterol/metabolismo , Internalización del Virus , Sustitución de Aminoácidos/genética , Animales , Virus Chikungunya/genética , Virus Chikungunya/crecimiento & desarrollo , Concentración de Iones de Hidrógeno , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo
6.
J Med Entomol ; 47(3): 421-35, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20496590

RESUMEN

Persistent West Nile virus (WNV) infection in the mosquito Culex quinquefasciatus Say (Diptera: Culicidae) is associated with pathological changes in the salivary glands, including apoptotic cell death and a corresponding reduction in virus transmission over time. The vector host response to WNV infection and the molecular basis of WNV pathogenesis in Cx. quinquefasciatus was investigated using oligonucleotide microarrays designed to detect differences in the salivary gland transcriptome between WNV-infected mosquitoes and uninfected controls. Transcripts with increased abundance in infected salivary glands included those related to immunity, transcription, protein transport and degradation, amino acid and nucleotide metabolism, signal transduction, and cellular detoxification. Microarray-based analysis detected a decrease in transcript levels of a Culex inhibitor of apoptosis gene (IAP-1) and a decrease in abundance of 11 transcripts encoding salivary gland proteins. Transcript levels for an endonuclease, a proline-rich mucin, and several D7 protein family members also decreased. Transcripts with the greatest change in abundance during infection had either no similarity to sequences found in GenBank, VectorBase, and FlyBase, or were similar to sequences with uncharacterized protein products. These transcripts represent exciting targets for future analysis. Results from this study suggest that WNV infection influences transcriptional changes in an invertebrate host target tissue that may confer an advantage to the replicating virus, induce a host defense response, and alter the composition of vector saliva. The ramifications of these changes are discussed in terms of mosquito vector competence and WNV pathogenesis.


Asunto(s)
Culex/genética , Perfilación de la Expresión Génica , Glándulas Salivales/fisiología , Transcripción Genética , Fiebre del Nilo Occidental/transmisión , Virus del Nilo Occidental/patogenicidad , Alimentación Animal , Animales , Culex/virología , ADN Complementario/genética , Regulación hacia Abajo , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Regulación hacia Arriba
7.
PLoS Pathog ; 3(12): e201, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18069894

RESUMEN

Chikungunya virus (CHIKV) is an emerging arbovirus associated with several recent large-scale epidemics. The 2005-2006 epidemic on Reunion island that resulted in approximately 266,000 human cases was associated with a strain of CHIKV with a mutation in the envelope protein gene (E1-A226V). To test the hypothesis that this mutation in the epidemic CHIKV (strain LR2006 OPY1) might influence fitness for different vector species, viral infectivity, dissemination, and transmission of CHIKV were compared in Aedes albopictus, the species implicated in the epidemic, and the recognized vector Ae. aegypti. Using viral infectious clones of the Reunion strain and a West African strain of CHIKV, into which either the E1-226 A or V mutation was engineered, we demonstrated that the E1-A226V mutation was directly responsible for a significant increase in CHIKV infectivity for Ae. albopictus, and led to more efficient viral dissemination into mosquito secondary organs and transmission to suckling mice. This mutation caused a marginal decrease in CHIKV Ae. aegypti midgut infectivity, had no effect on viral dissemination, and was associated with a slight increase in transmission by Ae. aegypti to suckling mice in competition experiments. The effect of the E1-A226V mutation on cholesterol dependence of CHIKV was also analyzed, revealing an association between cholesterol dependence and increased fitness of CHIKV in Ae. albopictus. Our observation that a single amino acid substitution can influence vector specificity provides a plausible explanation of how this mutant virus caused an epidemic in a region lacking the typical vector. This has important implications with respect to how viruses may establish a transmission cycle when introduced into a new area. Due to the widespread distribution of Ae. albopictus, this mutation increases the potential for CHIKV to permanently extend its range into Europe and the Americas.


Asunto(s)
Aedes/virología , Infecciones por Alphavirus/transmisión , Virus Chikungunya/genética , Virus Chikungunya/patogenicidad , Insectos Vectores/virología , Mutación , Infecciones por Alphavirus/epidemiología , Animales , Animales Lactantes , Chlorocebus aethiops , Cricetinae , Modelos Animales de Enfermedad , Femenino , Genoma Viral , Humanos , Ratones , Reunión/epidemiología , Sensibilidad y Especificidad , Células Vero
8.
Methods Mol Biol ; 1960: 191-205, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30798533

RESUMEN

Laboratory rodent influenza infection models have been and continue to be a critical tool for understanding virus-host interactions during infection. The incidence of seasonal influenza infections coupled with the need for novel therapeutics and universal vaccines highlights the need to uncover novel mechanisms of pathogenesis and protection. Mouse models are extremely useful for the evaluation of influenza vaccines and provide an invaluable tool to probe the immune response. This chapter describes the technique of intranasal inoculation of male C57BL/6J mice with an H1N1 strain of influenza (A/Puerto Rico/8/1934) and methods for assessing the optimum dose for infection, viral titers in lung tissue, and severity of disease.


Asunto(s)
Pulmón/inmunología , Infecciones por Orthomyxoviridae/inmunología , Administración Intranasal , Animales , Modelos Animales de Enfermedad , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/uso terapéutico , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/virología , Vacunación/métodos
9.
Sci Rep ; 9(1): 9711, 2019 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-31273220

RESUMEN

Hundreds of cellular host factors are required to support dengue virus infection, but their identity and roles are incompletely characterized. Here, we identify human host dependency factors required for efficient dengue virus-2 (DENV2) infection of human cells. We focused on two, TTC35 and TMEM111, which we previously demonstrated to be required for yellow fever virus (YFV) infection and others subsequently showed were also required by other flaviviruses. These proteins are components of the human endoplasmic reticulum membrane protein complex (EMC), which has roles in ER-associated protein biogenesis and lipid metabolism. We report that DENV, YFV and Zika virus (ZIKV) infections were strikingly inhibited, while West Nile virus infection was unchanged, in cells that lack EMC subunit 4. Furthermore, targeted depletion of EMC subunits in live mosquitoes significantly reduced DENV2 propagation in vivo. Using a novel uncoating assay, which measures interactions between host RNA-binding proteins and incoming viral RNA, we show that EMC is required at or prior to virus uncoating. Importantly, we uncovered a second and important role for the EMC. The complex is required for viral protein accumulation in a cell line harboring a ZIKV replicon, indicating that EMC participates in the complex process of viral protein biogenesis.


Asunto(s)
Infecciones por Flavivirus/virología , Flavivirus/patogenicidad , Interacciones Huésped-Patógeno , Proteínas de la Membrana/metabolismo , Biosíntesis de Proteínas , Internalización del Virus , Replicación Viral , Animales , Chlorocebus aethiops , Culicidae/virología , Retículo Endoplásmico , Humanos , Proteínas de la Membrana/genética , Células Tumorales Cultivadas , Células Vero
10.
Cell Host Microbe ; 25(6): 827-835.e6, 2019 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-31104946

RESUMEN

Viral glycoproteins are under constant immune surveillance by a host's adaptive immune responses. Antigenic variation including glycan introduction or removal is among the mechanisms viruses have evolved to escape host immunity. Understanding how glycosylation affects immunodominance on complex protein antigens may help decipher underlying B cell biology. To determine how B cell responses can be altered by such modifications, we engineered glycans onto the influenza virus hemagglutinin (HA) and characterized the molecular features of the elicited humoral immunity in mice. We found that glycan addition changed the initially diverse antibody repertoire into an epitope-focused, genetically restricted response. Structural analyses showed that one antibody gene family targeted a previously subdominant, occluded epitope at the head interface. Passive transfer of this antibody conferred Fc-dependent protection to influenza virus-challenged mice. These results have potential implications for next-generation viral vaccines aimed at directing B cell responses to preferred epitope(s).


Asunto(s)
Anticuerpos Antivirales/inmunología , Epítopos/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Polisacáridos/metabolismo , Animales , Anticuerpos Antivirales/metabolismo , Cristalografía por Rayos X , Epítopos/química , Epítopos/genética , Epítopos/metabolismo , Glicosilación , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Inmunización Pasiva , Subtipo H3N2 del Virus de la Influenza A/genética , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/prevención & control , Unión Proteica , Conformación Proteica , Análisis de Supervivencia
11.
J Control Release ; 270: 1-13, 2018 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-29170142

RESUMEN

Most FDA-approved adjuvants for infectious agents boost humoral but not cellular immunity, and have poorly-understood mechanisms. Stimulator of interferon genes (STING, also known as MITA, MPYS, or ERIS) is an exciting adjuvant target due to its role in cyclic dinucleotide (CDN)-driven anti-viral immunity; however, a major hindrance is STING's cytosolic localization which requires intracellular delivery of its agonists. As a result, STING agonists administered in a soluble form have elicited suboptimal immune responses. Delivery of STING agonists via particle platforms has proven a more successful strategy, but the opportunity for improved formulations and bioactivity remains. In this study we evaluated the adjuvant activity of the potent STING agonist, CDN 3'3'-cGAMP (cGAMP), encapsulated in acid-sensitive acetalated dextran (Ace-DEX) polymeric microparticles (MPs) which passively target antigen-presenting cells for intracellular release. This formulation was superior to all particle delivery systems evaluated and maintained its bioactivity following a sterilizing dose of gamma irradiation. Compared to soluble cGAMP, the Ace-DEX cGAMP MPs enhanced type-I interferon responses nearly 1000-fold in vitro and 50-fold in vivo, caused up to a 104-fold boost in antibody titers, increased Th1-associated responses, and expanded germinal center B cells and memory T cells. Furthermore, the encapsulated cGAMP elicited no observable toxicity in animals and achieved protective immunity against a lethal influenza challenge seven months post-immunization when using CDN adjuvant doses up to 100-fold lower than previous reports. For these reasons, Ace-DEX MP-encapsulated cGAMP represents a potent vaccine adjuvant of humoral and cellular immunity.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Proteínas de la Membrana/inmunología , Nucleótidos Cíclicos/administración & dosificación , Animales , Células Cultivadas , Dextranos/administración & dosificación , Femenino , Inmunidad Celular , Inmunidad Humoral , Masculino , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/administración & dosificación , Vacunación
12.
Am J Trop Med Hyg ; 76(3): 424-30, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17360862

RESUMEN

To evaluate the potential for nonviremic transmission (NVT) of West Nile virus (WNV) to occur in nature, we examined the effect of increasing spatial and temporal separation between co-feeding mosquitoes on the efficiency of nonviremic transmission and the potential of a West Nile virus bridge vector species, Aedes albopictus, to be infected via nonviremic transmission. West Nile virus-infected (donor) Culex pipiens quinquefasciatus were allowed to feed on a mouse for 5 minutes followed by non-infected (recipient) mosquitoes with increasing spatial (0, 10, 20, 30, 40, or 50 mm) or temporal (0, 15, 30, 45, or 60 min) separation from the site or time of donor feeding, respectively. Recipients became infected when feeding up to 40 mm from the donor and up to 45 minutes after donor feeding. Additionally, nonviremic transmission of West Nile virus from Cx. p. quinquefasciatus to Ae. albopictus was observed.


Asunto(s)
Aedes/virología , Culex/virología , Insectos Vectores/virología , Viremia/transmisión , Fiebre del Nilo Occidental/transmisión , Animales , Glándulas Salivales/virología , Factores de Tiempo
13.
Am J Trop Med Hyg ; 76(1): 118-28, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17255239

RESUMEN

The effect of long-term West Nile virus (WNV) infection on Culex salivary gland morphology and viability was evaluated by transmission electron microscopy during a four week period post-blood feeding. These studies showed that apoptosis and other cytopathologic changes occurred more frequently in WNV-infected mosquitoes compared with uninfected controls. The effect of long-term infection on WNV transmission was evaluated by titering virus in saliva over the same time period. Although the mean titer of WNV in mosquito saliva did not change significantly over time, the percentage of saliva samples containing WNV decreased. Because of the importance of saliva in blood meal acquisition and virus delivery, salivary gland pathology has the potential to affect mosquito feeding behavior and virus transmission. Results from this study add to a growing body of evidence that arbovirus infections in mosquito vectors can be cytopathic, and offer a potential mechanism for virus-induced cell death in mosquitoes.


Asunto(s)
Culex/virología , Efecto Citopatogénico Viral , Glándulas Salivales/citología , Glándulas Salivales/virología , Fiebre del Nilo Occidental/transmisión , Virus del Nilo Occidental/fisiología , Animales , Muerte Celular , Femenino , Fiebre del Nilo Occidental/patología , Fiebre del Nilo Occidental/veterinaria
14.
Vaccine ; 35(48 Pt B): 6664-6671, 2017 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-29056422

RESUMEN

BACKGROUND: Antipyretics reduce fever following childhood vaccinations; after inactivated influenza vaccine (IIV) they might ameliorate fever and thereby decrease febrile seizure risk, but also possibly blunt the immune response. We assessed the effect of antipyretics on immune responses and fever following IIV in children ages 6 through 47 months. METHODS: Over the course of three seasons, one hundred forty-two children, receiving either a single or the first of 2 recommended doses of IIV, were randomized to receive either oral acetaminophen suspension (n = 59) or placebo (n = 59) (double-blinded) or ibuprofen (n = 24) (open-label) immediately following IIV and every 4-8 h thereafter for 24 h. Blood samples were obtained at enrollment and 4 weeks following the last recommended IIV dose. Responses to IIV were assessed by hemagglutination inhibition assay (HAI). Seroprotection was defined as an HAI titer ≥1:40 and seroconversion as a titer ≥1:40 if baseline titer <1:10 or four-fold rise if baseline titer ≥1:10. Participants were monitored for fever and other solicited symptoms on the day of and day following IIV. RESULTS: Significant differences in seroconversion and post-vaccination seroprotection were not observed between children included in the different antipyretic groups and the placebo group for the vaccine antigens included in IIV over the course of the studies. Frequencies of solicited symptoms, including fever, were similar between treatment groups and the placebo group. CONCLUSIONS: Significant blunting of the immune response was not observed when antipyretics were administered to young children receiving IIV. Studies with larger sample sizes are needed to definitively establish the effect of antipyretics on IIV immunogenicity.


Asunto(s)
Antipiréticos/administración & dosificación , Fiebre/tratamiento farmacológico , Inmunidad Activa/efectos de los fármacos , Vacunas contra la Influenza/inmunología , Vacunas de Productos Inactivados/inmunología , Acetaminofén/administración & dosificación , Acetaminofén/efectos adversos , Acetaminofén/sangre , Anticuerpos Antivirales/sangre , Antipiréticos/efectos adversos , Antipiréticos/sangre , Antipiréticos/inmunología , Preescolar , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Inmunización Secundaria , Lactante , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/efectos adversos , Gripe Humana/prevención & control , Masculino , Convulsiones Febriles/tratamiento farmacológico , Convulsiones Febriles/prevención & control , Vacunación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/efectos adversos
15.
Am J Trop Med Hyg ; 75(5): 986-93, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17124001

RESUMEN

Four chimeric yellow fever (YF) 17D-dengue (DEN) candidate vaccine viruses (ChimeriVax-DEN; Acambis, Cambridge, MA) were characterized in Aedes aegypti and Ae. albopictus mosquitoes collected from Thailand. The four vaccine viruses contained the relevant prM and E genes of wild-type dengue viruses (DENV; serotypes 1-4) substituted for the equivalent genes in the YF vaccine virus (17D) backbone. Each chimera conferred protection against the homologous DENV serotype; a tetravalent mix of all four chimeras stimulates an immune response against all serotypes. Field-collected mosquitoes from Thailand were fed on blood containing each of the viruses under study and held 21 days after infection. Infection and dissemination rates were based on antigen detection in the body or head tissues, respectively. All four wild-type DENV serotypes infected and disseminated, but the candidate vaccine viruses were highly attenuated in mosquitoes with respect to infection and especially with respect to dissemination. Considering the low level viremias anticipated in humans vaccinated with these viruses, it is predicted that the risks of infection and transmission by mosquitoes in nature is minimal.


Asunto(s)
Aedes/virología , Quimera , Virus del Dengue/fisiología , Dengue/prevención & control , Vacunas contra el Virus del Nilo Occidental/administración & dosificación , Animales , Virus del Dengue/genética , Virus del Dengue/crecimiento & desarrollo , Virus del Dengue/inmunología , Insectos Vectores/virología , Tailandia , Replicación Viral
16.
Vector Borne Zoonotic Dis ; 6(4): 325-37, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17187566

RESUMEN

The recent outbreak of Chikungunya virus (CHIKV) on several islands in the Indian Ocean and in India has focused attention on this reemerging virus and highlighted the need for development of new tools to study vector-virus-host interactions. We have constructed and characterized, in cell culture, Aedes aegypti and Ae. albopictus mosquitoes, infectious cDNA clones of CHIKV using a recent isolate from La Réunion Island. Comparison of the growth kinetics and infection rates of the viral isolate CHIKV strain LR2006 OPY1 (CHIKV-LR) and a full-length infectious clone (CHIKV-LR ic) indicate that the infectious clone has retained the viral phenotypes of the original isolate. Infectious clones that express green fluorescent protein (GFP) were also produced and characterized in cell culture and in Aedes mosquitoes. The CHIKV-LR 5'GFP infected Ae. aegypti and Ae. albopictus mosquitoes at a similar rate to the original virus and to the full length infectious clone. The CHIKV-LR 3'GFP only infected Ae. albopictus mosquitoes at similar rates. The development of these authentic infectious clones will enable targeted studies of the molecular determinants of infection, pathogenesis and transmission competence by Ae. aegypti and Ae. albopictus mosquitoes.


Asunto(s)
Aedes/virología , Infecciones por Alphavirus/virología , Virus Chikungunya/patogenicidad , Genoma Viral , Insectos Vectores/virología , Infecciones por Alphavirus/epidemiología , Infecciones por Alphavirus/prevención & control , Infecciones por Alphavirus/transmisión , Animales , Virus Chikungunya/clasificación , Virus Chikungunya/genética , Brotes de Enfermedades , Genotipo , Proteínas Fluorescentes Verdes/genética , Humanos , Cinética , Filogenia , Reunión/epidemiología
17.
Clin Vaccine Immunol ; 23(7): 648-51, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27146001

RESUMEN

Modified vaccinia Ankara virus (MVA) is a smallpox vaccine candidate. This study was performed to determine if MVA vaccination provides long-term protection against rabbitpox virus (RPXV) challenge, an animal model of smallpox. Two doses of MVA provided 100% protection against a lethal intranasal RPXV challenge administered 9 months after vaccination.


Asunto(s)
Vacuna contra Viruela/administración & dosificación , Vacuna contra Viruela/inmunología , Viruela/prevención & control , Virus Vaccinia/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Esquemas de Inmunización , Conejos , Análisis de Supervivencia
18.
Cell Host Microbe ; 18(1): 86-95, 2015 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-26159721

RESUMEN

Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure-based vaccine development.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , Fiebre Chikungunya/terapia , Virus Chikungunya/inmunología , Inmunización Pasiva/métodos , Animales , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/aislamiento & purificación , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/aislamiento & purificación , Quimioprevención/métodos , Virus Chikungunya/fisiología , Modelos Animales de Enfermedad , Humanos , Concentración 50 Inhibidora , Ratones , Unión Proteica , Análisis de Supervivencia , Resultado del Tratamiento , Proteínas del Envoltorio Viral/inmunología , Internalización del Virus/efectos de los fármacos
19.
Nat Med ; 20(8): 927-35, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25064127

RESUMEN

Oxidative tissue injury often accompanies viral infection, yet there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic RNA viruses. Lipid peroxidation, regulated in part through sphingosine kinase-2, severely restricts HCV replication in Huh-7 cells and primary human hepatoblasts. Endogenous oxidative membrane damage lowers the 50% effective concentration of direct-acting antivirals in vitro, suggesting critical regulation of the conformation of the NS3-4A protease and the NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to transmembrane and membrane-proximal residues within these proteins and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain of HCV. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence.


Asunto(s)
Hepacivirus/enzimología , Peroxidación de Lípido , Estrés Oxidativo , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Antivirales/farmacología , Línea Celular , Membrana Celular/patología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatocitos/metabolismo , Hepatocitos/virología , Humanos , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas no Estructurales Virales/genética
20.
Virology ; 426(1): 22-33, 2012 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-22314017

RESUMEN

West Nile virus NS4B is a small hydrophobic nonstructural protein approximately 27 kDa in size whose function is poorly understood. Amino acid substitutions were introduced into the NS4B protein primarily targeting two distinct regions; the N-terminal domain (residues 35 through 60) and the central hydrophobic domain (residues 95 through 120). Only the NS4B P38G substitution was associated with both temperature-sensitive and small-plaque phenotypes. Importantly, this mutation was found to attenuate neuroinvasiveness greater than 10,000,000-fold and lower viremia titers compared to the wild-type NY99 virus in a mouse model. Full genome sequencing of the NS4B P38G mutant virus revealed two unexpected mutations at NS4B T116I and NS3 N480H (P38G/T116I/N480H), however, neither mutation alone was temperature sensitive or attenuated in mice. Following incubation of P38G/T116I/N480H at 41°C, five mutants encoding compensatory substitutions in the NS4B protein exhibited a reduction in the temperature-sensitive phenotype and reversion to a virulent phenotype in the mouse model.


Asunto(s)
Mutación Missense , Proteínas no Estructurales Virales/genética , Virus del Nilo Occidental/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Análisis Mutacional de ADN , Femenino , Humanos , Ratones , Datos de Secuencia Molecular , Alineación de Secuencia , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Virulencia , Virus del Nilo Occidental/química , Virus del Nilo Occidental/crecimiento & desarrollo , Virus del Nilo Occidental/patogenicidad
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