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1.
Clin Exp Immunol ; 170(3): 321-32, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23121673

RESUMEN

Common variable immunodeficiency (CVID), the most frequent symptomatic immunoglobulin primary immunodeficiency, is associated with chronic T cell activation and reduced frequency of CD4(+) T cells. The underlying cause of immune activation in CVID is unknown. Microbial translocation indicated by elevated serum levels of lipopolysaccharide and soluble CD14 (sCD14) has been linked previously to systemic immune activation in human immunodeficiency virus/acquired immune deficiency syndrome (HIV-1/AIDS), alcoholic cirrhosis and other conditions. To address the mechanisms of chronic immune activation in CVID, we performed a detailed analysis of immune cell populations and serum levels of sCD14, soluble CD25 (sCD25), lipopolysaccharide and markers of liver function in 35 patients with CVID, 53 patients with selective immunoglobulin (Ig)A deficiency (IgAD) and 63 control healthy subjects. In CVID subjects, the concentration of serum sCD14 was increased significantly and correlated with the level of sCD25, C-reactive protein and the extent of T cell activation. Importantly, no increase in serum lipopolysaccharide concentration was observed in patients with CVID or IgAD. Collectively, the data presented suggest that chronic T cell activation in CVID is associated with elevated levels of sCD14 and sCD25, but not with systemic endotoxaemia, and suggest involvement of lipopolysaccharide-independent mechanisms of induction of sCD14 production.


Asunto(s)
Inmunodeficiencia Variable Común/sangre , Inmunodeficiencia Variable Común/inmunología , Endotoxemia/inmunología , Subunidad alfa del Receptor de Interleucina-2/sangre , Receptores de Lipopolisacáridos/sangre , Adolescente , Adulto , Anciano , Linfocitos B/inmunología , Bronquiectasia/sangre , Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , Endotoxemia/sangre , Femenino , Granuloma/sangre , Humanos , Deficiencia de IgA/sangre , Deficiencia de IgA/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Receptores de Lipopolisacáridos/inmunología , Lipopolisacáridos/sangre , Lipopolisacáridos/inmunología , Hepatopatías/sangre , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Esplenomegalia/sangre , Linfocitos T/inmunología , Adulto Joven
2.
Nat Med ; 6(10): 1140-6, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11017146

RESUMEN

Prolonged antiretroviral therapy (ART) is not likely to eradicate human immunodeficiency virus type I (HIV-I) infection. Here we explore the effect of therapeutic immunization in the context of ART during primary infection using the simian immunodeficiency virus (SIV251) macaque model. Vaccination of rhesus macaques with the highly attenuated poxvirus-based NYVAC-SIV vaccine expressing structural genes elicited vigorous virus-specific CD4 + and CD8+ T cell responses in macaques that responded effectively to ART. Following discontinuation of a six-month ART regimen, viral rebound occurred in most animals, but was transient in six of eight vaccinated animals. Viral rebound was also transient in four of seven mock-vaccinated control animals. These data establish the importance of antiretroviral treatment during primary infection and demonstrate that virus-specific immune responses in the infected host can be expanded by therapeutic immunization.


Asunto(s)
Antivirales/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Vacunas Sintéticas/farmacología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Productos del Gen gag/genética , Macaca mulatta , Poxviridae/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Vacunación , Vacunas Atenuadas/farmacología , Viremia/tratamiento farmacológico
3.
Nat Med ; 7(12): 1320-6, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11726972

RESUMEN

Given the mucosal transmission of HIV-1, we compared whether a mucosal vaccine could induce mucosal cytotoxic T lymphocytes (CTLs) and protect rhesus macaques against mucosal infection with simian/human immunodeficiency virus (SHIV) more effectively than the same vaccine given subcutaneously. Here we show that mucosal CTLs specific for simian immunodeficiency virus can be induced by intrarectal immunization of macaques with a synthetic-peptide vaccine incorporating the LT(R192G) adjuvant. This response correlated with the level of T-helper response. After intrarectal challenge with pathogenic SHIV-Ku2, viral titers were eliminated more completely (to undetectable levels) both in blood and intestine, a major reservoir for virus replication, in intrarectally immunized animals than in subcutaneously immunized or control macaques. Moreover, CD4+ T cells were better preserved. Thus, induction of CTLs in the intestinal mucosa, a key site of virus replication, with a mucosal AIDS vaccine ameliorates infection by SHIV in non-human primates.


Asunto(s)
Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vacunas contra el SIDA/administración & dosificación , Administración Rectal , Secuencia de Aminoácidos , Animales , Epítopos de Linfocito T/inmunología , Productos del Gen gag/inmunología , Productos del Gen pol/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Macaca mulatta , Datos de Secuencia Molecular , Recto/virología , Linfocitos T Citotóxicos , Linfocitos T Colaboradores-Inductores , Vacunación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/uso terapéutico , Carga Viral
4.
Gene Ther ; 16(11): 1300-13, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19641529

RESUMEN

B-cell-based cellular vaccines represent a promising approach to active immunotherapy of cancer complementing the use of dendritic cells, especially in pediatric patients and patients with low bone marrow reserves. B cells can be easily prepared in large numbers and readily home to secondary lymphoid organs, the primary site of induction of cytotoxic T lymphocyte (CTL) responses. However, most B-cell-based vaccines tested so far failed to induce functional and protective CTLs in in vivo models. Here, we show that B-cells activated through the toll-like receptor-9 (TLR-9) and CD40 up-regulate surface expression of major histocompatibility complex and costimulatory molecules, produce IL-12, and exhibit potent antigen-presenting properties in vitro. Importantly, although administration of peptide-coated or transiently transfected B cells fails to induce immune responses, therapeutic immunization with low numbers of genetically modified B cells stably expressing antigen results in an induction of functional CTLs and protection against the growth of tumor in an animal model. After activation, B cells partially loose their ability to home to organized lymphoid tissue because of the shedding of CD62L; however, this property can be restored by expression of protease-resistant mutant of CD62L. In summary, the data presented in this report suggest that genetically modified activated B cells represent a promising candidate for a cancer vaccine eliciting functional systemic CTLs.


Asunto(s)
Linfocitos B/trasplante , Vacunas contra el Cáncer/inmunología , Linfocitos T Citotóxicos/inmunología , Timoma/prevención & control , Neoplasias del Timo/prevención & control , Animales , Presentación de Antígeno/inmunología , Antígenos de Superficie/metabolismo , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Citotoxicidad Inmunológica/inmunología , Interleucina-12/inmunología , Activación de Linfocitos/inmunología , Transfusión de Linfocitos/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Timoma/inmunología , Timoma/patología , Neoplasias del Timo/inmunología , Neoplasias del Timo/patología , Receptor Toll-Like 9/inmunología , Células Tumorales Cultivadas
5.
Mol Cell Biol ; 16(10): 5579-90, 1996 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8816470

RESUMEN

The production of tumor necrosis factor alpha (TNF-alpha), a key proinflammatory cytokine essential for the function of the immune system, is regulated at both the transcriptional and posttranscriptional levels. In this report, we focus on the interaction of TNF-alpha mRNA with macrophage proteins, likely mediators of its post-transcriptional control. Mapping of murine TNF-alpha mRNA by using a combination of RNase protection and RNA gel shift assays revealed that two distinct sites within the 3' untranslated region (3'-UTR) engage in the formation of four major RNA-protein complexes, while no protein binding to the 5'-UTR or coding sequences was detected. The protein-binding site of three RNA-protein complexes, A, B, and C, is positioned between bases 1291 and 1320 inside the AU-rich sequence, a region previously shown to be crucial for both translational repression and lipopolysaccharide inducibility of TNF-alpha. An additional protein complex (complex D) whose binding to the TNF-alpha 3'-UTR was independent of the presence of AU-rich sequences was identified. At least six protein species with apparent molecular masses of 48, 52, 54, 81, 101, and 150 kDa are in direct contact with TNF-alpha mRNA. The RNA-binding proteins are differentially distributed in the cell: complexes A and D are present predominantly in the cytosol, while complexes B and C are found in the nucleus and associated with particulate cytoplasmic fractions. Cytosolic complex A displays comparatively high specificity for TNF-alpha mRNA, while the binding of complexes B and C to TNF-alpha mRNA is readily competed for by other AU-rich sequence-containing RNAs. In summary, these findings demonstrate that two regions of the TNF-alpha mRNA molecule interact with macrophage RNA-binding protein complexes that differ in their core protein composition, cellular distribution, and affinity to TNF-alpha mRNA.


Asunto(s)
Macrófagos/inmunología , ARN Mensajero/química , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Citoplasma/metabolismo , Ratones , Datos de Secuencia Molecular , Mutagénesis Insercional , Proteínas Nucleares/metabolismo , Biosíntesis de Proteínas , Sondas ARN , ARN Mensajero/biosíntesis , Transcripción Genética
6.
Nucleic Acids Res ; 29(4): 863-71, 2001 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-11160917

RESUMEN

Tumor necrosis factor alpha (TNFalpha) acts as a beneficial mediator in the process of host defence. In recent years major interest has focused on the AU-rich elements (AREs) present in the 3'-untranslated region (3'-UTR) of TNFalpha mRNA as this region plays a pivotal role in post-transcriptional control of TNFalpha production. Certain stimuli, such as lipopolysaccharides, a component of the Gram-negative bacterial cell wall, have the ability to relinquish the translational suppression of TNFalpha mRNA imposed by these AREs in macrophages, thereby enabling the efficient production of the TNFalpha. In this study we show that the polymorphism (GAU trinucleotide insertional mutation) present in the regulatory 3'-UTR of TNFalpha mRNA of NZW mice results in the hindered binding of RNA-binding proteins, thereby leading to a significantly reduced production of TNFalpha protein. We also show that the binding of macrophage proteins to the main ARE is also decreased by another trinucleotide (CAU) insertion in the TNFalpha 3'-UTR. One of the proteins affected by the GAU trinucleotide insertional mutation was identified as HuR, a nucleo-cytoplasmic shuttling protein previously shown to play a prominent role in the stability and translatability of mRNA containing AREs. Since binding of this protein most likely modulates the stability, translational efficiency and transport of TNFalpha mRNA, these results suggest that mutations in the ARE of TNFalpha mRNA decrease the production of TNFalpha protein in macrophages by hindering the binding of HuR to the ARE.


Asunto(s)
Regiones no Traducidas 3'/genética , Regiones no Traducidas 3'/metabolismo , Antígenos de Superficie , Polimorfismo Genético/genética , Proteínas de Unión al ARN/metabolismo , Factor de Necrosis Tumoral alfa/genética , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Dactinomicina/farmacología , Proteínas ELAV , Proteína 1 Similar a ELAV , Ensayo de Inmunoadsorción Enzimática , Femenino , Interferón gamma/farmacología , Lipopolisacáridos/farmacología , Sustancias Macromoleculares , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos , Mutagénesis Insercional/genética , Unión Proteica/efectos de los fármacos , Sondas ARN/genética , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/biosíntesis
7.
DNA Cell Biol ; 21(9): 619-26, 2002 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12396604

RESUMEN

Most vaccine modalities for human immunodeficiency virus type 1 (HIV-1) tested for immunogenicity and efficacy in the SIVmac (simian immunodeficiency virus) macaque model do not include the viral regulatory proteins. Because viral regulatory proteins are expressed early during the virus life cycle and represent an additional source of antigens, their inclusion as a vaccine component may increase the overall virus-specific immune response in vaccinees. However, at least two of the early proteins, Tat and Nef, may be immunosuppressive, limiting their usefulness as components of an SIV vaccine. We have constructed a polyvalent chimeric protein in which the open reading frames for Tat and Nef have been reassorted and the nuclear localization sequence for Tat and Rev and the myristoylation site for Nef have been removed. The resulting DNA plasmid (pDNA-SIV-Retanef) (pDNA-SIV-RTN) encodes a protein of 55 kDa (Retanef) that localizes at the steady state in the cytoplasma of transfected cells. Both the DNA-SIV-RTN and the highly attenuated recombinant poxvirus vector NYVAC-SIV-RTN were demonstrated to be immunogenic in SIVmac251-infected macaques treated with ART as well as in naive macaques. An equivalent strategy may be used for the generation of polyvalent antigens encoding the regulatory proteins in a HIV-1 vaccine candidate.


Asunto(s)
Secuencias Reguladoras de Ácidos Nucleicos , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas/inmunología , Animales , Productos del Gen gag/metabolismo , Genes nef/inmunología , Genes rev/inmunología , Genes tat/inmunología , Células HeLa , Humanos , Macaca mulatta , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Vacunas Sintéticas/inmunología , Proteínas Reguladoras y Accesorias Virales/genética , Proteínas Reguladoras y Accesorias Virales/inmunología
8.
BMC Infect Dis ; 1: 9, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11504564

RESUMEN

BACKGROUND: HIV-I can be transmitted by intravenous inoculation of contaminated blood or blood product or sexually through mucosal surfaces. Here we performed a pilot study in the SIVmac251 macaque model to address whether the route of viral entry influences the kinetics of the appearance and the size of virus-specific immune in different tissue compartments. METHODS: For this purpose, of 2 genetically defined Mamu-A*01-positive macaques, 1 was exposed intravenously and the other intrarectally to the same SIVmac251 viral stock and virus-specific CD8+ T-cells were measured within the first 12 days of infection in the blood and at day 12 in several tissues following euthanasia. RESULTS: Virus-specific CD8+ T-cell responses to Gag, Env, and particularly Tat appeared earlier in the blood of the animal exposed by the mucosal route than in the animal exposed intravenously. The magnitude of these virus-specific responses was consistently higher in the systemic tissues and GALT of the macaque exposed by the intravenous route, suggesting a higher viral burden in the tissues as reflected by the faster appearance of virus in plasma. Differences in the ability of the virus-specific CD8+ T-cells to respond in vitro to specific peptide stimulation were also observed and the greatest proliferative ability was found in the GALT of the animal infected by the intrarectal route. CONCLUSIONS: These data may suggest that the natural mucosal barrier may delay viral spreading. The consequences of this observation, if confirmed in studies with a larger number of animals, may have implications in vaccine development.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , División Celular , Modelos Animales de Enfermedad , Macaca mulatta/genética , Proyectos Piloto , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología
9.
Nucleic Acids Res ; 26(11): 2803-12, 1998 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-9592171

RESUMEN

Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine regulator of an early immune response and the central mediator of deleterious effects of systemic inflammatory response syndrome. High production of TNF-alpha by macrophages requires two signals: the first signal induces transcription, while the second signal releases the translational repression of TNF-alpha mRNA. The translational control of TNF-alpha expression is conferred by sequences in the 3'-untranslated region (3'-UTR) of its mRNA. Previously, we have characterized protein complexes binding to the main AU-rich region in the 3'-UTR of murine TNF-alpha mRNA. Here we describe a second protein binding region which is located 147 bases downstream of the first region and interacts with at least seven distinct protein species present in murine macrophages. The second protein binding motif contains a single AUAUUUAU sequence motif; a mutation of this sequence to AUAGGUAU abrogates the binding of proteins. Some of the macrophage proteins mutually compete for the binding to both regions, while others seem to be region specific. The existence of the two protein binding domains explains the previously published data addressing the translatibility of a reporter gene linked to various deletion mutants of the TNF-alpha 3'-UTR. Both the sequence and position of the two putative protein binding regions are highly conserved across species, indicating their important role in the regulation of translational repression and inducibility of TNF-alpha synthesis.


Asunto(s)
ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Factor de Necrosis Tumoral alfa/genética , Adenina , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Secuencia Conservada , Humanos , Ratones , Datos de Secuencia Molecular , Biosíntesis de Proteínas , ARN Complementario , Conejos , Ratas , Homología de Secuencia de Ácido Nucleico , Especificidad de la Especie , Uridina
10.
Eur J Biochem ; 251(3): 734-43, 1998 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-9490047

RESUMEN

Mice of diverse genetic backgrounds may be classified as being either resistant or susceptible to infection with Mycobacteria. These phenotypes appear to be determined by a single gene on chromosome 1, the Bcg gene, and are expressed at the level of the macrophage in vitro. When compared to macrophages from mice of the susceptible phenotype (Bcg[s]), macrophages from mice of the resistant phenotype (Bcg[r]) show enhanced functional properties including increased expression of MHC class II molecules, increased nitric oxide production, and greater capacity to inhibit the growth of several intracellular pathogens. The bacteriostatic activity of B10R and B10S macrophages correlated with the amount of nitric oxide produced by the macrophages. Since protein kinase C (PKC) has been shown to be involved in the induction of a range of macrophage functional activities, experiments were conducted to examine the possibility that phenotypic differences between Bcg(r) and Bcg(s) macrophages may be related to differences in PKC-dependent signalling. Macrophage cell lines were derived from mice congenic at the Bcg locus that are either resistant (B10R) or susceptible (B10S) to infection with Mycobacteria. In the basal state, PKC-specific activity was significantly increased in the cytosolic fractions of B10R cells when compared to B10S cells. Following phorbol myristate acetate (PMA) treatment and following the stimulation with Mycobacteria bovis BCG, PKC-specific activity increased significantly in membrane fractions of both B10R and B10S cells, but the absolute level was significantly greater in particulate fractions from B10R macrophages. Furthermore, B10R cells had a superior ability to phosphorylate endogenous substrates compared to B10S macrophages. Scatchard analysis of phorbol ester receptors revealed no differences between B10R and B10S cells. In contrast, the sensitivity of partially purified PKC from B10S cells to activation in vitro by diacylglycerol was decreased by approximately 50% when compared to enzyme from B10R cells. Western-blotting analysis using antibodies specific for PKC isoforms (alpha, beta, delta, epsilon, zeta and eta) showed similar levels of PKC isoforms present in B10R and B10S cells. To examine whether differences in PKC activity of B10R and B10S cells had functional consequences, the induction of c-fos gene expression was compared in the two cell lines. In response either to infection with M. bovis BCG or to stimulation with PMA, c-fos mRNA levels in B10R macrophages were increased 2-4-fold in comparison to B10S macrophages. Since we have previously found that the bacteriostatic activity of B10R and B10S macrophages correlated with the amount of nitric oxide produced by the macrophages, we have tested if the enhancement of PKC activity in these macrophages affects their ability to produce nitric oxide. We have found that interferon-gamma-(IFNgamma)-induced secretion of nitric oxide by B10R macrophages could be augmented a few fold by the activation of PKC whereas, in B10S macrophages stimulated with IFNgamma, nitric oxide release could be augmented by only about 10-20%. These results indicate that the differences in PKC activity between B10R and B10S macrophages may contribute to altered responsiveness to IFNgamma that results in different production of effector molecules crucial for bacteriostatic activity against M. bovis BCG.


Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Macrófagos/fisiología , Proteínas de la Membrana/genética , Proteína Quinasa C/metabolismo , Transducción de Señal , Animales , Células de la Médula Ósea , Proteínas Portadoras/biosíntesis , Línea Celular , Susceptibilidad a Enfermedades , Antígenos de Histocompatibilidad Clase II/biosíntesis , Cinética , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Proteínas de la Membrana/biosíntesis , Ratones , Ratones Endogámicos , Mycobacterium bovis , Fenotipo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , ARN Mensajero/biosíntesis , Acetato de Tetradecanoilforbol/farmacología , Transcripción Genética/efectos de los fármacos
11.
J Virol ; 75(23): 11483-95, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11689630

RESUMEN

The identification of several simian immunodeficiency virus mac251 (SIV(mac251)) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8(+) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIV(mac251) and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4(+) T cells. The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8(+) T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIV(mac251) that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIV(mac251)-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8(+) T-cell function.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Productos del Gen gag/inmunología , VIH/inmunología , Inmunidad Mucosa , Especificidad de Órganos , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Recuento de Linfocito CD4 , Células Cultivadas , Quimera , Ensayo de Inmunoadsorción Enzimática , VIH/fisiología , Interferón gamma/biosíntesis , Macaca mulatta , Virus de la Inmunodeficiencia de los Simios/fisiología , Factor de Necrosis Tumoral alfa/biosíntesis , Viremia , Replicación Viral
12.
J Virol ; 76(1): 292-302, 2002 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11739694

RESUMEN

T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination- and infection-induced T-cell responses are dependent on the host major histocompatibility complex classes I and II (MHC-I and MHC-II) antigens. Here we report that both inherent, host-dependent immune responses to SIVmac251 infection and vaccination-induced immune responses to viral antigens were able to reduce virus replication and/or CD4+ T-cell loss. Both the presence of the MHC-I Mamu-A*01 genotype and vaccination of rhesus macaques with ALVAC-SIV-gag-pol-env (ALVAC-SIV-gpe) contributed to the restriction of SIVmac251 replication during primary infection, preservation of CD4+ T cells, and delayed disease progression following intrarectal challenge exposure of the animals to SIV(mac251 (561)). ALVAC-SIV-gpe immunization induced cytotoxic T-lymphocyte (CTL) responses cumulatively in 67% of the immunized animals. Following viral challenge, a significant secondary virus-specific CD8+ T-cell response was observed in the vaccinated macaques. In the same immunized macaques, a decrease in virus load during primary infection (P = 0.0078) and protection from CD4 loss during both acute and chronic phases of infection (P = 0.0099 and P = 0.03, respectively) were observed. A trend for enhanced survival of the vaccinated macaques was also observed. Neither boosting the ALVAC-SIV-gpe with gp120 immunizations nor administering the vaccine by the combination of mucosal and systemic immunization routes increased significantly the protective effect of the ALVAC-SIV-gpe vaccine. While assessing the role of MHC-I Mamu-A*01 alone in the restriction of viremia following challenge of nonvaccinated animals with other SIV isolates, we observed that the virus load was not significantly lower in Mamu-A*01-positive macaques following intravenous challenge with either SIV(mac251 (561)) or SIV(SME660). However, a significant delay in CD4+ T-cell loss was observed in Mamu-A*01-positive macaques in each group. Of interest, in the case of intravenous or intrarectal challenge with the chimeric SIV/HIV strains SHIV(89.6P) or SHIV(KU2), respectively, MHC-I Mamu-A*01-positive macaques did not significantly restrict primary viremia. The finding of the protective effect of the Mamu-A*01 molecule parallels the protective effect of the B*5701 HLA allele in HIV-1-infected humans and needs to be accounted for in the evaluation of vaccine efficacy against SIV challenge models.


Asunto(s)
Productos del Gen env/administración & dosificación , Productos del Gen gag/administración & dosificación , Productos del Gen pol/administración & dosificación , Antígenos de Histocompatibilidad Clase I/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunación , Vacunas Virales/administración & dosificación , Animales , Productos del Gen env/inmunología , Productos del Gen gag/inmunología , Productos del Gen pol/inmunología , Macaca , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus Vaccinia , Vacunas Virales/inmunología
13.
J Immunol ; 167(12): 7180-91, 2001 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-11739541

RESUMEN

T cell-mediated immune responses play an important role in the containment of HIV-1 replication. Therefore, an effective vaccine against HIV-1 should be able to elicit high frequencies of virus-specific CD8(+) and CD4(+) T cells. The highly attenuated poxvirus-based vaccine candidate, NYVAC-SIV-gag-pol-env (NYVAC-SIV-gpe), has been shown to induce and/or expand SIV-specific CD4(+) and CD8(+) T cell responses in both naive and infected macaques. In this study, the immunogenicity of NYVAC-SIV-gpe alone was compared with a combination regimen where priming with an optimized DNA-SIV-gag-env vaccine candidate was followed by a NYVAC-SIV-gpe boost. In macaques immunized with the prime-boost regimen, the extent and durability of CD8(+) T cell response to an immunodominant SIV gag epitope was increased and these animals recognized a broader array of subdominant SIV epitopes in the cytolytic assay. In addition, the prime-boost regimen significantly enhanced the proliferative responses to both SIV gag and env proteins. Thus, the combination of these vaccine modalities may represent a valuable strategy in the development of a vaccine for HIV.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas Virales/inmunología , Animales , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Células Cultivadas , Pruebas Inmunológicas de Citotoxicidad , Esquemas de Inmunización , Inmunización Secundaria , Interferón gamma/biosíntesis , Cinética , Activación de Linfocitos , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/genética , Vacunas Atenuadas/inmunología , Vacunas de ADN/inmunología
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