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1.
AIDS Res Hum Retroviruses ; 27(9): 933-43, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21332419

RESUMEN

The availability of an effective vaginal microbicide would be a major step toward containment of HIV transmission as well as allowing women self-protection against HIV infection. Here we evaluated the efficacy of vaginal application of the potent nonnucleoside reverse transcriptase inhibitor (NNRTI) MC 1220 against vaginal challenge of macaques with RT-SHIV, a chimeric simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT) gene of HIV-1. Challenge infection of monkeys with RT-SHIV currently represents the only nonhuman primate model available to test the anti-HIV-1 effects of NNRTIs. Two different gel formulations containing different MC 1220 concentrations were evaluated for efficacy in female rhesus macaques exposed to RT-SHIV. Five groups of five animals each were treated with two different gel compositions containing no drug, 0.1% or 0.5% MC 1220, followed by vaginal RT-SHIV challenge 30 min later. One animal in each group treated with the low concentration of MC 1220 as well as one control animal remained uninfected after vaginal challenge. By contrast, three of the animals receiving 0.5% MC 1220 remained uninfected, suggesting a threshold of the drug. Despite being negative for plasma viral RNA and absence of seroconversion, almost all uninfected animals exhibited SIV-specific T cells, either in the periphery or in lymph nodes draining the portal of virus entry. Our results make MC 1220 a promising compound for further development as a topical microbicide and warrant additional testing with improved formulation, long-lasting vaginal delivery systems, or even combinations with other inhibitors.


Asunto(s)
Antiinfecciosos Locales/administración & dosificación , Transmisión de Enfermedad Infecciosa/prevención & control , Pirimidinonas/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Administración Intravaginal , Animales , Femenino , Fluorobencenos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , Macaca mulatta , Recombinación Genética , Virus de la Inmunodeficiencia de los Simios/genética , Resultado del Tratamiento
2.
Vaccine ; 26(51): 6690-8, 2008 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-18694796

RESUMEN

To evaluate the efficacy of a multigenic vaccine and its protective immunity in the SIVmac239 challenge model, 12 rhesus macaques were divided into two groups. The vaccine group was intramuscularly immunized with multigenic DNA and recombinant adenovirus vaccine, while the control group received buffers. At 16 weeks after the last immunization, all macaques were challenged orally with pathogenic SIVmac239. The mean plasma SIV RNA loads of the vaccine group were significantly lower than those of the placebo control group up to 16 weeks post-challenge. The vaccine-induced Gag-specific IFN-gamma ELISPOT T cell responses inversely correlated with the viral loads before the chronic phase. Two out of six vaccinated macaques with strong and sustained Gag-specific T cell responses showed viremia control and maintained CD4+ T cell percentage. However, the other four vaccinated macaques showed high viral loads and reduced level of CD4+ T cell percentages during the chronic phase, comparable to those in control macaques. Five out of six vaccinated macaques survived for more than 72 weeks, while five out of six controls died of an AIDS-related disease. Therefore, the vaccination conferred not only reduction of viral loads in a portion of vaccinated macaques (2/6), but also prolonged survival of all vaccinated macaques regardless of viremia control. Our results further suggest that new experimental approaches may be needed to assess protective effects from AIDS-associated disease in the immunized macaques after oral SIV challenge.


Asunto(s)
Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Productos del Gen gag/inmunología , Inmunidad Celular , Macaca mulatta , Vacunas contra el SIDAS/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/inmunología , Carga Viral , Viremia/inmunología , Viremia/virología , Replicación Viral
3.
J Virol ; 81(23): 13180-90, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17898066

RESUMEN

The development of needle-free vaccines is one of the recently defined "grand challenges in global health" (H. Varmus, R. Klausner, R. Klausner, R. Zerhouni, T. Acharya, A. S. Daar, and P. A. Singer, Science 302:398-399, 2003). To explore whether a natural pathway to the inductive site of the mucosa-associated lymphatic tissue could be exploited for atraumatic immunization purposes, replication-deficient viral vector vaccines were sprayed directly onto the tonsils of rhesus macaques. Tonsillar immunization with viral vector vaccines encoding simian immunodeficiency virus (SIV) antigens induced cellular and humoral immune responses. Viral RNA levels after a stringent SIV challenge were reduced, providing a level of protection similar to that observed after systemic immunization with the same vaccines. Thus, atraumatic oral spray immunization with replication-deficient vectors can overcome the epithelial barrier, deliver the vaccine antigen to the mucosa-associated lymphatic tissue, and avoid induction of tolerance, providing a novel approach to circumvent acceptability problems of syringe and needle vaccines for children and in developing countries.


Asunto(s)
Administración Oral , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/inmunología , Animales , Macaca mulatta , Tonsila Palatina/inmunología , ARN Viral/sangre , Vacunas contra el SIDAS/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Carga Viral
4.
J Med Primatol ; 36(4-5): 195-205, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17669208

RESUMEN

BACKGROUND: Due to an ever increasing shortage of rhesus macaques of Indian origin (InR) that have been generally used for preclinical AIDS vaccine trials in non-human primates, demand is rising for Chinese rhesus macaques (ChR). However, the immunogenicity of an AIDS vaccine candidate has not been compared in parallel in both rhesus macaque subspecies. METHODS: ChR and InR were immunized with SIV/HIV DNA and adenovirus vaccine and their immune responses to SIV and HIV evaluated. RESULTS: SIV Gag- and Env-specific T-cell responses and SIV-specific lymphoproliferative responses measured in ChR were significantly weaker than those in InR (P < 0.05). By contrast, antibody responses to SIV Env, Tat, and Nef in ChR were stronger than those in InR (P < 0.05). CONCLUSIONS: Immunogenicity of an AIDS vaccine can vary significantly depending on the geographic origin implying genetic differences of macaques. This must be considered when describing and interpreting results of such vaccine studies.


Asunto(s)
Inmunización/veterinaria , Macaca mulatta , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas de ADN/inmunología , Animales , Anticuerpos Antivirales/sangre , Área Bajo la Curva , Proliferación Celular , China , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática/veterinaria , Inmunización/métodos , India , Interferón gamma/análisis , Pruebas de Neutralización/veterinaria , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Estadísticas no Paramétricas , Linfocitos T/inmunología , Linfocitos T/virología , Vacunas Sintéticas/inmunología
5.
Front Biosci ; 12: 2107-23, 2007 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-17127448

RESUMEN

Elucidating the mechanisms that protect monkeys previously immunized with attenuated SIV (SIVDeltanef) against challenge infection with pathogenic virus may reveal new strategies for the development of an effective HIV vaccine. Here we show that a single atraumatic application of SIVDeltanef to the tonsils of four rhesus macaques conferred protection against SIVmac251 applied intrarectally 26 weeks later. While this protection was not complete, i.e., challenge virus could be isolated from all immunized animals, it was reflected by significantly lower viral loads in the blood (weeks 2-16 after challenge, p < 0.01) and considerably lower loads in lymphoid organs, and more stable peripheral CD4 counts in a proportion of the immunized animals as compared to four non-immunized, SIVmac251-infected control monkeys. SIV-specific humoral as well as systemic and mucosal T cell responses were detected in the immunized animals, but there was no correlation between their magnitude of expression and the level of protection. Analyses of leukocyte subsets in these animals at necropsy (24 weeks after challenge) did not reveal a significantly enhanced proportion of gamma/delta T cells in the tissues of protected monkeys. Therefore, tonsillar application of attenuated SIV induces protection in some animals against a superinfection with wild-type SIV distant at a distant mucosal site.


Asunto(s)
Vacunas contra el SIDAS , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Antivirales/sangre , Linfocitos T CD4-Positivos/inmunología , Femenino , Eliminación de Gen , Genes nef , Inmunidad Celular , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Ganglios Linfáticos/virología , Macaca mulatta , Masculino , Tonsila Palatina/virología , ARN Viral/análisis , Receptores de Antígenos de Linfocitos T gamma-delta/análisis , Recto/virología , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/genética , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología
6.
Viral Immunol ; 19(3): 448-57, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16987063

RESUMEN

As part of a European multicenter study designed to determine the optimal combination and order of a mixed-modality vaccine against acquired immunodeficiency syndrome, rhesus monkeys received a combination of three different vectors, all expressing the same Simian Immunodeficiency Virus (SIV) genes followed by mucosal challenge with highly pathogenic SIV. In the study reported here, animals were primed with DNA followed by one booster immunization with Semliki Forest Virus (SFV) and two immunizations with modified Vaccinia Ankara (MVA). To address the relevance of mucosal immunization, we compared systemic versus a combination of systemic and mucosal antigen application. Although all vaccinees became infected after intrarectal challenge with SIV, most (six of eight) were protected from profound loss of CD4+ cells. In addition, vaccinees showed lower viral loads than did controls (p < 0.05). Overall, these protective effects were more pronounced in those animals whose schedule included immunization via the mucosa. In summary, the vaccine regimen used here achieved one important criterion of efficacy: the suppression of disease development as indicated by conservation of CD4+ cells.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Vacunas contra el SIDAS/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Administración Rectal , Animales , Anticuerpos Antivirales/sangre , Vectores Genéticos , Inmunización , Inmunización Secundaria , Macaca mulatta , Vacunas contra el SIDAS/genética , Virus de los Bosques Semliki/genética , Virus de los Bosques Semliki/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Vacunas de ADN , Virus Vaccinia/genética , Virus Vaccinia/inmunología
7.
J Virol ; 80(9): 4469-81, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16611907

RESUMEN

Point mutations in SIVmac239 Nef disrupting CD4 downmodulation and enhancement of virion infectivity attenuate viral replication in acutely infected rhesus macaques, but changes selected later in infection fully restore Nef function (A. J. Iafrate et al., J. Virol. 74:9836-9844, 2000). To further evaluate the relevance of these Nef functions for viral persistence and disease progression, we analyzed an SIVmac239 Nef mutant containing a deletion of amino acids Q64 to N67 (delta64-67Nef). This mutation inactivates the N-distal AP-2 clathrin adaptor binding element and disrupts the abilities of Nef to downregulate CD4, CD28 and CXCR4 and to stimulate viral replication in vitro. However, it does not impair the downmodulation of CD3 and class I major histocompatibility complex (MHC-I) or MHC-II and the upregulation of the MHC-II-associated invariant chain, and it has only a moderate effect on the enhancement of virion infectivity. Replication of the delta64-67Nef variant in acutely infected macaques was intermediate between grossly nef-deleted and wild-type SIVmac239. Subsequently, three of six macaques developed moderate to high viral loads and developed disease, whereas the remaining animals efficiently controlled SIV replication and showed a more attenuated clinical course of infection. Sequence analysis revealed that the deletion in nef was not repaired in any of these animals. However, some changes that slightly enhanced the ability of Nef to downmodulate CD4 and moderately increased Nef-mediated enhancement of viral replication and infectivity in vitro were observed in macaques developing high viral loads. Our results imply that both the Nef functions that were disrupted by the delta64-67 mutation and the activities that remained intact contribute to viral pathogenicity.


Asunto(s)
Complejo 2 de Proteína Adaptadora/metabolismo , Productos del Gen nef/química , Productos del Gen nef/metabolismo , Macaca mulatta/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Replicación Viral , Enfermedad Aguda , Alelos , Secuencia de Aminoácidos , Animales , Sitios de Unión , Línea Celular , Productos del Gen nef/genética , Variación Genética/genética , Humanos , Infecciones por Lentivirus/genética , Infecciones por Lentivirus/metabolismo , Infecciones por Lentivirus/virología , Macaca mulatta/genética , Datos de Secuencia Molecular , Unión Proteica , Alineación de Secuencia , Factores de Tiempo
8.
Virology ; 351(1): 133-44, 2006 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-16616946

RESUMEN

Vaccination with exogenous antigens such as recombinant viral proteins, immunodeficiency virus-derived whole inactivated virus particles, or virus-like particles (VLP) has generally failed to provide sufficient protection in animal models for AIDS. Pseudotyping VLPs with the vesicular stomatitis virus G protein (VSV-G), which is known to mediate entry into dendritic cells, might allow more efficient stimulation of immune responses. Therefore, we pseudotyped noninfectious immunodeficiency virus-like particles with VSV-G and carried out a preliminary screen of their immunogenicity and vaccination efficacy. Incorporation of VSV-G into HIV-1 VLPs led to hundred-fold higher antibody titers to HIV-1 Gag and enhancement of T cell responses in mice. Repeated vaccination of rhesus monkeys for 65 weeks with VSV-G pseudotyped simian immunodeficiency virus (SIV)-like particles (VLP[G]) provided initial evidence for efficient suppression of viral load after mucosal challenge with the SIVmac239 virus. Challenge of monkeys after a 28 week vaccination regimen with VLP[G] led to a reduction in peak viremia, but persistent suppression of viral load was not achieved. Due to limitations in the number of animals available for this study, improved efficacy of VSV-G pseudotyped VLPs in nonhuman primates could not be demonstrated. However, mouse experiments revealed that pseudotyping of VLPs with fusion-competent VSV-G clearly improves their immunogenicity. Additional strategies, particularly adjuvants, should be considered to provide greater protection against a challenge with pathogenic immunodeficiency virus.


Asunto(s)
Vacunas contra el SIDA/inmunología , Glicoproteínas de Membrana/inmunología , Virus de la Estomatitis Vesicular Indiana , Proteínas del Envoltorio Viral/inmunología , Vacunas contra el SIDA/administración & dosificación , Animales , Línea Celular , Esquema de Medicación , Anticuerpos Anti-VIH/sangre , Humanos , Macaca mulatta/inmunología , Glicoproteínas de Membrana/genética , Ratones , ARN Viral/sangre , Factores de Tiempo , Proteínas del Envoltorio Viral/genética , Carga Viral , Virión/genética , Virión/inmunología
9.
Vaccine ; 24(11): 1811-20, 2006 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-16274888

RESUMEN

In this study, we investigated the ability of a multigenic SIV DNA prime/replication-defective adenovirus serotype 5 (rAd/SIV) boost regimen to induce SIV-specific immune responses and protection against intrarectal challenge with SIVmac251 in rhesus macaques. Four rhesus macaques were immunized intramuscularly three times at 8-week intervals with SIV DNA vaccine and boosted once with rAd/SIV vaccine Four control macaques received the same amount of mock plasmid DNA and mock adenovirus vector. While the SIV DNA vaccine included plasmids expressing a mutated human IL-12 gene (IL-12N222L) as well as SIVmac239 structural and regulatory genes, the rAd/SIV vaccine contained rAd vectors expressing SIVmac239 genes only. Immunization with SIV DNA vaccine alone induced SIV-specific IFN-gamma ELISPOT responses in only two of four vaccinated macaques, whereas all animals developed SIV-specific T-cell responses and Env- and Tat-specific antibody responses following the rAd/SIV vaccine boost. Upon intrarectal challenge with pathogenic SIVmac251, strong anamnestic Env-specific binding and neutralizing antibody responses were detected in the vaccinated macaques. Overall, the immunized macaques had lower peak and set-point viral loads than control macaques, suggesting that the induced immune responses play a role in the control of viremia. In addition, the loss of CD4+ T cells was delayed in the vaccinated macaques after challenge. These results indicate that the multigenic DNA prime-adenovirus boost immunization may be a promising approach in developing an effective AIDS vaccine.


Asunto(s)
Anticuerpos Antivirales/sangre , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas de ADN/inmunología , Adenoviridae/genética , Adenoviridae/inmunología , Adyuvantes Inmunológicos , Animales , Recuento de Linfocito CD4 , Vectores Genéticos , Inmunización Secundaria , Inyecciones Intramusculares , Interferón gamma/biosíntesis , Interleucina-12/genética , Interleucina-12/farmacología , Macaca mulatta , Pruebas de Neutralización , Plásmidos , Vacunas contra el SIDAS/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Linfocitos T/inmunología , Vacunación , Vacunas de ADN/administración & dosificación , Carga Viral , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/inmunología , Proteínas Estructurales Virales/genética , Proteínas Estructurales Virales/inmunología , Viremia
10.
J Immunol ; 170(12): 5861-8, 2003 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-12794111

RESUMEN

Adoptive immunotherapy with CTL against minor histocompatibility Ags (mHA) provides a promising way to treat leukemia relapse in allogeneic chimeras. Here we describe the in vitro generation of CTL against mHA in the dog. We tested their inhibitory effect on the growth of hemopoietic progenitor cells stimulated by hemopoietic growth factors in a 4-day suspension culture. CTL were produced by coculture of donor PBMC with bone marrow-derived dendritic cells (DCs). These DCs were characterized by morphology, high expression of MHC class II and CD1a, and the absence of the monocyte-specific marker CD14. Characteristically these cells stimulated allogeneic lymphocytes (MLR) and, after pulsing with a foreign Ag (keyhole limpet hemocyanin), autologous T cells. CTL were generated either ex vivo by coculture with DCs of DLA-identical littermates or in vivo by immunization of the responder with DCs obtained from a DLA-identical littermate. In suspension culture assays the growth of hemopoietic progenitor cells was inhibited in 53% of DLA-identical littermate combinations. In canine families mHA segregated with DLA as restriction elements. One-way reactivity against mHA was found in five littermate combinations. In two cases mHA might be Y chromosome associated, in three cases autosomally inherited alleles were detected. We conclude that CTL can be produced in vitro and in vivo against mHA on canine hemopoietic progenitor cells using bone marrow-derived DCs.


Asunto(s)
Células Madre Hematopoyéticas/inmunología , Antígenos de Histocompatibilidad Menor/inmunología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , División Celular/genética , División Celular/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/trasplante , Perros , Epítopos de Linfocito T/inmunología , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Inmunofenotipificación , Prueba de Cultivo Mixto de Linfocitos , Masculino , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo , Antígenos de Histocompatibilidad Menor/fisiología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/trasplante , Linfocitos T Reguladores/inmunología
11.
Vet Immunol Immunopathol ; 84(1-2): 61-70, 2002 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-11825598

RESUMEN

Dogs are used in preclinical transplantation models to study methods of allogeneic bone marrow transplantation (BMT). The evaluation of chimerism is of major significance for the investigation of graft-vs.-host (GvH) and host-vs.-graft (HvG) reactions. To detect and quantitate male donor cells after a sex-mismatched (male to female) allogeneic BMT, we established a semi-quantitative polymerase chain reaction (PCR) assay. Based on the canine Y-chromosome sex-determining region (Sry) sequence, we designed primer specific for the detection of male DNA and optimised PCR conditions and cycle numbers. Artificial mixtures of male and female leukocytes were used to analyse the sensitivity of the assay. To validate our established method, we determined the percentage of chimerism in three transplanted female dogs. Under optimised conditions, the established PCR assay specifically detected male cells down to 0.01%, which corresponds to 0.1ng of transplanted male DNA. The percentage of chimerism could be quantitated either by agarose gel analysis or Southern blot analysis. Using our assay, we could confirm the percentage of chimerism in blood samples of three transplanted female canines, previously determined by karyotype analysis as 0, 100 and 100%, respectively. The established semi-quantitative PCR assay offers a quick, simple, accurate and sensitive way of evaluating and quantitating the percentage of chimerism in a sex-mismatched canine BMT model.


Asunto(s)
Trasplante de Médula Ósea , Genes sry , Reacción en Cadena de la Polimerasa/métodos , Animales , Quimera , Perros , Femenino , Masculino , Sensibilidad y Especificidad
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