Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 36
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Proc Natl Acad Sci U S A ; 117(30): 18002-18009, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32665438

RESUMO

In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti-HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1-infected humanized mice and one pivotal experiment in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25-45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.


Assuntos
Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/imunologia , Imunoglobulina G/imunologia , Receptores de IgG/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Modelos Animais de Doenças , Infecções por HIV/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Testes de Neutralização
2.
PLoS Pathog ; 15(5): e1007776, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31083697

RESUMO

VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4ß7 mAb (Rh-α4ß7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4ß7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4ß7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4ß7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4ß7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4ß7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4ß7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4ß7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4ß7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais/farmacologia , Integrinas/antagonistas & inibidores , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vagina/efeitos dos fármacos , Viremia/prevenção & controle , Animais , Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Quimioterapia Combinada , Feminino , Anticorpos Anti-HIV , Integrinas/imunologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Vagina/imunologia , Vagina/virologia , Viremia/imunologia , Viremia/virologia
3.
Proc Natl Acad Sci U S A ; 115(1): E62-E71, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29255022

RESUMO

Mycobacterium tuberculosis continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that M. tuberculosis utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of M. tuberculosis in macrophages in vivo by CD4+ T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4+ T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Triptofano/imunologia , Tuberculoma/imunologia , Tuberculose Pulmonar/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Granuloma/imunologia , Granuloma/patologia , Pulmão/patologia , Macaca mulatta , Macrófagos/imunologia , Macrófagos/patologia , Mycobacterium tuberculosis/patogenicidade , Tuberculoma/patologia , Tuberculose Pulmonar/patologia
4.
J Infect Dis ; 221(9): 1398-1406, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175822

RESUMO

BACKGROUND: MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is a novel reverse transcriptase-translocation inhibitor. METHODS: We assessed MK-8591 as preexposure prophylaxis in the rhesus macaque model of intrarectal challenge with simian/human immunodeficiency virus (SHIV). In study 1, 8 rhesus macaques received 3.9 mg/kg of MK-8591 orally on day 0 and once weekly for the next 14 weeks. Eight controls were treated with vehicle. All rhesus macaques were challenged with SHIV109CP3 on day 6 and weekly for up to 12 challenges or until infection was confirmed. The dose of MK-8591 was reduced to 1.3 and 0.43 mg/kg/week in study 2 and further to 0.1 and 0.025 mg/kg/week in study 3. In studies 2 and 3, each dose was given up to 6 times once weekly, and animals were challenged 4 times once weekly with SHIV109CP3. RESULTS: Control macaques were infected after a median of 1 challenge (range, 1-4 challenges). All treated animals in studies 1 and 2 were protected, consistent with a 41.5-fold lower risk of infection (P < .0001, by the log-rank test). In study 3, at a 0.1-mg/kg dose, 2 rhesus macaques became infected, consistent with a 7.2-fold lower risk of infection (P = .0003, by the log-rank test). The 0.025-mg/kg dose offered no protection. CONCLUSIONS: These data support MK-8591's potential as a preexposure prophylaxis agent.


Assuntos
Desoxiadenosinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Administração Retal , Animais , Macaca mulatta , Masculino , Reto/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia
5.
J Med Primatol ; 49(4): 188-201, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32285485

RESUMO

BACKGROUND: This study evaluated the feasibility of trio housing caged adult male rhesus macaques and attempted to identify outcome predictors for trio housing formation and its intermediary introduction steps. METHODS: Subjects were familiarized consecutively to each potential group member via protected contact prior to introduction into the trio. Seven trios were attempted, involving 18 males, with three males attempted in two different trios. RESULTS: One group was deemed successful, with a tenure of 51 days. Five were disbanded within minutes, and one was deemed unsuccessful the following morning. Two males sustained wounds requiring veterinary care over the course of the study. Outcome of the protected contact phase was predicted by age and temperament disparities as well as initial behavior. CONCLUSIONS: While outcomes were poor, it suggests that attempts can be made relatively safely, and alternative introduction strategies should be explored to increase the feasibility of trio housing for adult males.


Assuntos
Agressão , Criação de Animais Domésticos/métodos , Abrigo para Animais/estatística & dados numéricos , Macaca mulatta/psicologia , Comportamento Social , Animais , Masculino
6.
J Immunol ; 200(2): 810-820, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29196458

RESUMO

Infusion of a simianized anti-α4ß7 mAb (Rh-α4ß7) just before and following SIV infection protected rhesus macaques from developing AIDS and partially from vaginal SIV acquisition. Recently, short-term treatment with Rh-α4ß7 in combination with cART was found to lead to prolonged viral suppression after withdrawal of all therapeutic interventions. The humanized form of Rh-α4ß7, vedolizumab, is a highly effective treatment for inflammatory bowel disease. To clarify the mechanism of action of Rh-α4ß7, naive macaques were infused with Rh-α4ß7 and sampled in blood and tissues before and after treatment to monitor several immune cell subsets. In blood, Rh-α4ß7 increased the CD4+ and CD8+ T cell counts, but not B cell counts, and preferentially increased CCR6+ subsets while decreasing CD103+ and CD69+ lymphocytes. In mucosal tissues, surprisingly, Rh-α4ß7 did not impact integrin α4+ cells, but decreased the frequencies of CCR6+ and CD69+ CD4+ T cells and, in the gut, Rh-α4ß7 transiently decreased the frequency of memory and IgA+ B cells. In summary, even in the absence of inflammation, Rh-α4ß7 impacted selected immune cell subsets in different tissues. These data provide new insights into the mechanisms by which Rh-α4ß7 may mediate its effect in SIV-infected macaques with implications for understanding the effect of treatment with vedolizumab in patients with inflammatory bowel disease.


Assuntos
Integrinas/antagonistas & inibidores , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Mucosa/imunologia , Mucosa/metabolismo , Receptores CCR6/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Macaca mulatta , Especificidade de Órgãos/imunologia
7.
J Immunol ; 194(5): 2415-23, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25624458

RESUMO

The tissue microenvironment shapes the characteristics and functions of dendritic cells (DCs), which are important players in HIV infection and dissemination. Notably, DCs in the gut have the daunting task of orchestrating the balance between immune response and tolerance. They produce retinoic acid (RA), which imprints a gut-homing phenotype and influences surrounding DCs. To investigate how the gut microenvironment impacts the ability of DCs to drive HIV infection, we conditioned human immature monocyte-derived DCs (moDCs) with RA (RA-DCs), before pulsing them with HIV and mixing them with autologous T cells. RA-DCs showed a semimature, mucosal-like phenotype and released higher amounts of TGF-ß1 and CCL2. Using flow cytometry, Western blot, and microscopy, we determined that moDCs express the cell adhesion molecule mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) and that RA increases its expression. MAdCAM-1 was also detected on a small population of DCs in rhesus macaque (Macaca mulata) mesenteric lymph node. RA-DCs formed more DC-T cell conjugates and promoted significantly higher HIV replication in DC-T cell mixtures compared with moDCs. This correlated with the increase in MAdCAM-1 expression. Blocking MAdCAM-1 partially inhibited the enhanced HIV replication. In summary, RA influences DC phenotype, increasing their ability to exacerbate HIV infection. We describe a previously unknown mechanism that may contribute to rapid HIV spread in the gut, a major site of HIV replication after mucosal exposure.


Assuntos
Células Dendríticas/efeitos dos fármacos , Infecções por HIV/imunologia , HIV-1/imunologia , Mucosa Intestinal/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Moléculas de Adesão Celular , Quimiocina CCL2/biossíntese , Quimiocina CCL2/metabolismo , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Feminino , Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Linfonodos/imunologia , Linfonodos/patologia , Linfonodos/virologia , Macaca mulatta , Mucoproteínas/genética , Mucoproteínas/imunologia , Fenótipo , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T/virologia , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/metabolismo , Tretinoína/imunologia , Replicação Viral
8.
J Immunol ; 193(4): 1799-811, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25024382

RESUMO

Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag-specific CD4 and CD8 T cells in the lung. The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans. In this study, we used an aerosol vaccination strategy to administer AERAS-402, a replication-defective recombinant adenovirus (rAd) type 35 expressing Mycobacterium tuberculosis Ags Ag85A, Ag85B, and TB10.4, in bacillus Calmette-Guérin (BCG)-primed or unprimed rhesus macaques. Immunization with BCG generated low purified protein derivative-specific CD4 T cell responses in blood and bronchoalveolar lavage. In contrast, aerosolized AERAS-402 alone or following BCG induced potent and stable Ag85A/b-specific CD4 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN-γ, as well as TNF and IL-2. Such responses induced by BCG, AERAS-402, or both failed to confer overall protection following challenge with 275 CFUs M. tuberculosis Erdman, although vaccine-induced responses associated with reduced pathology were observed in some animals. Anamnestic T cell responses to Ag85A/b were not detected in blood of immunized animals after challenge. Overall, our data suggest that a high M. tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model. However, the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens, alternative rAd serotypes with enhanced immunogenicity, and a physiological challenge dose may achieve protection against M. tuberculosis.


Assuntos
Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/prevenção & controle , Vacinação/métodos , Vacinas Sintéticas/imunologia , Aciltransferases/imunologia , Administração por Inalação , Animais , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Celular , Interferon gama/biossíntese , Interleucina-2/biossíntese , Pulmão/imunologia , Pulmão/microbiologia , Macaca mulatta , Masculino , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/virologia , Vacinas contra a Tuberculose/administração & dosagem , Tuberculose Pulmonar/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Vacinas de DNA , Vacinas Sintéticas/administração & dosagem
9.
Am J Respir Crit Care Med ; 191(10): 1185-96, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25730547

RESUMO

RATIONALE: Hypoxia promotes dormancy by causing physiologic changes to actively replicating Mycobacterium tuberculosis. DosR controls the response of M. tuberculosis to hypoxia. OBJECTIVES: To understand DosR's contribution in the persistence of M. tuberculosis, we compared the phenotype of various DosR regulon mutants and a complemented strain to M. tuberculosis in macaques, which faithfully model M. tuberculosis infection. METHODS: We measured clinical and microbiologic correlates of infection with M. tuberculosis relative to mutant/complemented strains in the DosR regulon, studied lung pathology and hypoxia, and compared immune responses in lung using transcriptomics and flow cytometry. MEASUREMENTS AND MAIN RESULTS: Despite being able to replicate initially, mutants in DosR regulon failed to persist or cause disease. On the contrary, M. tuberculosis and a complemented strain were able to establish infection and tuberculosis. The attenuation of pathogenesis in animals infected with the mutants coincided with the appearance of a Th1 response and organization of hypoxic lesions wherein M. tuberculosis expressed dosR. The lungs of animals infected with the mutants (but not the complemented strain) exhibited early transcriptional signatures of T-cell recruitment, activation, and proliferation associated with an increase of T cells expressing homing and proliferation markers. CONCLUSIONS: Delayed adaptive responses, a hallmark of M. tuberculosis infection, not only lead to persistence but also interfere with the development of effective antituberculosis vaccines. The DosR regulon therefore modulates both the magnitude and the timing of adaptive immune responses in response to hypoxia in vivo, resulting in persistent infection. Hence, DosR regulates key aspects of the M. tuberculosis life cycle and limits lung pathology.


Assuntos
Proteínas de Bactérias/genética , Hipóxia/metabolismo , Mycobacterium tuberculosis/genética , Proteínas Quinases/genética , Regulon/genética , Tuberculose/genética , Animais , Proteínas de Bactérias/imunologia , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Macaca mulatta , Mycobacterium tuberculosis/imunologia , Proteínas Quinases/imunologia , Regulon/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle
10.
J Med Primatol ; 43(3): 206-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24517274

RESUMO

BACKGROUND: A rhesus macaque developed chronic anemia, lymphocytic leukocytopenia, fever, and anorexia while immunodeficient following inoculation with a simian-human immunodeficiency virus. METHODS: A complete blood count, peripheral blood smear, polymerase chain reaction and gene sequence were performed. RESULTS: Blood smears demonstrated persistent intraerythrocytic piroplasms with rare Maltese cross forms. Babesia microti-like protozoa were confirmed by polymerase chain reaction and sequencing of the 18S ribosomal RNA gene. CONCLUSION: With continued use of non-human primates as models for human diseases, infection and complications from babesiosis should be monitored.


Assuntos
Animais de Laboratório , Babesia microti/isolamento & purificação , Babesiose/diagnóstico , Macaca mulatta , Doenças dos Macacos/diagnóstico , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Animais , Babesia microti/genética , Babesiose/parasitologia , DNA de Protozoário/genética , Feminino , HIV-1/fisiologia , Dados de Sequência Molecular , Doenças dos Macacos/parasitologia , Doenças dos Macacos/virologia , Reação em Cadeia da Polimerase , RNA Ribossômico 18S/genética , Análise de Sequência de DNA , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia
11.
J Infect Dis ; 207(7): 1115-27, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23255564

RESUMO

BACKGROUND: The BCG vaccine is ineffective against adult tuberculosis. Hence, new antituberculosis vaccines are needed. Correlates of protection against tuberculosis are not known. We studied the effects of BCG vaccination on gene expression in tuberculosis granulomas using macaques. METHODS: Macaques were BCG-vaccinated or sham-vaccinated and then challenged with virulent Mycobacterium tuberculosis. Lung lesions were used for comparative transcriptomics. RESULTS: Vaccinated macaques were protected with lower bacterial burden and immunopathology. Lesions from BCG-vaccinated nonhuman primates (NHPs) showed a better balance of α- and ß-chemokine gene expression with higher levels of ß-chemokine expression relative to nonvaccinated animals. Consistent with this, sham-vaccinated macaques recruited fewer macrophages relative to neutrophils in their lungs. The expression of indoleamine 2,3-dioxygenase (IDO), a known immunosuppressor, was significantly higher in both week 5 and 10 lesions from sham-vaccinated, relative to BCG-vaccinated, NHPs. IDO expression was primarily limited to the nonlymphocytic region of the lesions, within the inner ring structure surrounding the central necrosis. CONCLUSIONS: Our study defines lung gene expression correlates of protective response against tuberculosis, relative to disease, which can potentially be employed to assess the efficacy of candidate antituberculosis vaccines. Mycobacterium tuberculosis may modulate protective immune responses using diverse mechanisms, including increased recruitment of inflammatory neutrophils and the concomitant use of IDO to modulate inflammation.


Assuntos
Vacina BCG/uso terapêutico , Granuloma/imunologia , Granuloma/microbiologia , Imunomodulação , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/terapia , Animais , Vacina BCG/imunologia , Carga Bacteriana , Quimiocinas CC/imunologia , Quimiocinas CXC/imunologia , Progressão da Doença , Regulação Enzimológica da Expressão Gênica , Granuloma/enzimologia , Granuloma/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macaca fascicularis , Macrófagos/imunologia , Mycobacterium tuberculosis/patogenicidade , Necrose/imunologia , Necrose/microbiologia , Neutrófilos/imunologia , Fatores de Tempo , Transcriptoma , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Vacinação
12.
J Infect Dis ; 205(8): 1203-13, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22402035

RESUMO

BACKGROUND: Sigma H (sigH) is a major Mycobacterium tuberculosis (Mtb) stress response factor. It is induced in response to heat, oxidative stress, cell wall damage, and hypoxia. Infection of macrophages with the Δ-sigH mutant generates more potent innate immune response than does infection with Mtb. The mutant is attenuated for pathology in mice. METHODS: We used a nonhuman primate (NHP) model of acute tuberculosis, to better understand the phenotype of the Δ-sigH mutant in vivo. NHPs were infected with high doses of Mtb or the mutant, and the progression of tuberculosis was analyzed in both groups using clinical, pathological, microbiological, and immunological parameters. RESULTS: Animals exposed to Mtb rapidly progressed to acute pulmonary tuberculosis as indicated by worsening clinical correlates, high lung bacterial burden, and granulomatous immunopathology. All the animals rapidly succumbed to tuberculosis. On the other hand, the NHPs exposed to the Mtb:Δ-sigH mutant did not exhibit acute tuberculosis, instead showing significantly blunted disease. These NHPs survived the entire duration of the study. CONCLUSIONS: The Mtb:Δ-sigH mutant is completely attenuated for bacterial burden as well as immunopathology in NHPs. SigH and its regulon are required for complete virulence in primates. Further studies are needed to identify the molecular mechanism of this attenuation.


Assuntos
Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica/fisiologia , Pulmão/imunologia , Pulmão/microbiologia , Mycobacterium tuberculosis/metabolismo , Fator sigma/metabolismo , Tuberculose Pulmonar/microbiologia , Animais , Proteínas de Bactérias/genética , Perfilação da Expressão Gênica , Granuloma , Imuno-Histoquímica , Macaca mulatta , Mycobacterium tuberculosis/genética , Fator sigma/genética , Tuberculose Pulmonar/patologia
13.
J Med Primatol ; 40(4): 233-43, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21781131

RESUMO

BACKGROUND: Tuberculosis (TB) and AIDS together present a devastating public health challenge. Over 3 million deaths every year are attributed to these twin epidemics. Annually, ∼11 million people are coinfected with HIV and Mycobacterium tuberculosis (Mtb). AIDS is thought to alter the spontaneous rate of latent TB reactivation. METHODOLOGY: Macaques are excellent models of both TB and AIDS. Therefore, it is conceivable that they can also be used to model coinfection. Using clinical, pathological, and microbiological data, we addressed whether latent TB infection in rhesus macaques can be reactivated by infection with simian immunodeficiency virus (SIV). RESULTS: A low-dose aerosol infection of rhesus macaques with Mtb caused latent, asymptomatic TB infection. Infection of macaques exhibiting latent TB with a rhesus-specific strain of SIV significantly reactivated TB. CONCLUSIONS: Rhesus macaques are excellent model of TB/AIDS coinfection and can be used to study the phenomena of TB latency and reactivation.


Assuntos
Tuberculose Latente/complicações , Tuberculose Latente/fisiopatologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Administração por Inalação , Animais , Temperatura Corporal , Peso Corporal , Proteína C-Reativa/análise , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Macaca mulatta , Mycobacterium tuberculosis , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/fisiopatologia
14.
Vaccine X ; 8: 100105, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34258576

RESUMO

Development of intranasal vaccines for HIV-1 and other mucosal pathogens has been hampered by the lack of adjuvants that can be given safely to humans. We have found that an intranasal Shigella vaccine (Invaplex) which is well tolerated in humans can also function as an adjuvant for intranasal protein and DNA vaccines in mice. To determine whether Invaplex could potentially adjuvant similar vaccines in humans, we simultaneously administered a simian immunodeficiency virus (SIV) envelope (Env) protein and DNA encoding simian-human immunodeficiency virus (SHIV) with or without Invaplex in the nasal cavity of female rhesus macaques. Animals were intranasally boosted with adenoviral vectors expressing SIV env or gag,pol to evaluate memory responses. Anti-SIV antibodies in sera and nasal, genital tract and rectal secretions were quantitated by ELISA. Intracellular cytokine staining was used to measure Th1-type T cells in blood. Macaques given DNA/protein immunizations with 0.5 mg Invaplex developed greater serum IgG, nasal IgA and cervicovaginal IgA responses to SIV Env and SHIV Gag,Pol proteins when compared to non-adjuvanted controls. Rectal IgA responses to Env were only briefly elevated and not observed to Gag,Pol. Invaplex increased frequencies of IFNγ-producing CD4 and CD8 T cells to the Env protein, but not T cell responses induced by the DNA. Ad-SIV boosting increased Env-specific polyfunctional T cells and Env- and Gag,Pol-specific antibodies in serum and all secretions. The data suggest that Invaplex could be highly effective as an adjuvant for intranasal protein vaccines in humans, especially those intended to prevent infections in the genital or respiratory tract.

15.
Sci Transl Med ; 13(607)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408080

RESUMO

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4ß7 with an anti-α4ß7 monoclonal antibody (Rh-α4ß7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4ß7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4ß7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4ß7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4ß7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.


Assuntos
Infecções por HIV , HIV-1 , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Amplamente Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV/tratamento farmacológico , Integrinas , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico
16.
Front Immunol ; 11: 565746, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178191

RESUMO

Nonhuman primates (NHPs) in research institutions may be housed in a variety of social settings, such as group housing, pair housing or single housing based on the needs of studies. Furthermore, housing may change over the course of studies. The effects of housing and changes in housing on cell activation and vaccine mediated immune responses are not well documented. We hypothesized that animals moved indoors from group to single housing (GH-SH) would experience more stress than those separated from groups into pair housing (GH-PH), or those placed briefly into pair housing and separated 5 weeks later into single housing (GH-PH-SH). We also compared the effects of separation from group to pair housing with the separation from pair to single housing. Eighteen male rhesus macaques were followed over the course of changes in housing condition over 10-14 weeks, as well as prior to and after primary vaccination with a commercially available measles vaccine. We identified two phenotypic biomarkers, namely total CD8 population and proliferating B cells, that differed significantly across treatment groups over time. At 10 weeks post-separation, levels of proliferating B cells were higher in GH-SH subjects compared to GH-PH subjects, and in the latter, levels were lower at 10 weeks than prior to removal from group housing. At 2 weeks post-separation from group to single housing, the frequency of CD8+ T cells was higher in GH-SH subjects compared to one week post separation from pair into single housing in the GH-PH-SH subjects. Comparing the same elapsed time since the most recent separation activated CD20 populations were persistently higher in the GH-SH animals than the GH-PH-SH animals. Housing configuration did not influence vaccine-mediated responses. Overall, our study found benefits of pair housing over single housing, suggesting that perturbations in immune function will be more severe following separation from group to single housing than from pair to single housing, and supporting the use of short-duration pair housing even when animals must subsequently be separated. These findings are useful for planning the housing configurations of research NHPs used for vaccine studies and other studies where immune response is being assessed.


Assuntos
Criação de Animais Domésticos/métodos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Abrigo para Animais , Vacina contra Sarampo/administração & dosagem , Animais , Macaca mulatta , Masculino
17.
Front Pediatr ; 8: 388, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32766187

RESUMO

Background: Clinical measurements commonly used to evaluate overall health of laboratory animals including complete blood count, serum chemistry, weight, and immunophenotyping, differ with respect to age, development, and environment. This report provides comprehensive clinical and immunological reference ranges for pediatric rhesus macaques over the first year of life. Methods: We collected and analyzed blood samples from 151 healthy rhesus macaques, aged 0-55 weeks, and compared mother-reared infants to two categories of nursery-reared infants; those on an active research protocol and those under derivation for the expanded specific-pathogen-free breeding colony. Hematology was performed on EDTA-anticoagulated blood using a Sysmex XT2000i, and serum clinical chemistry was performed using the Beckman AU480 chemistry analyzer. Immunophenotyping of whole blood was performed with immunofluorescence staining and subsequent flow cytometric analysis on a BD LSRFortessa. Plasma cytokine analysis was performed using a Millipore multiplex Luminex assay. Results: For hematological and chemistry measurements, pediatric reference ranges deviate largely from adults. Comparison of mother-reared and nursery-reared animals revealed that large differences depend on rearing conditions and diet. Significant differences found between two nursery-reared cohorts (research and colony animals) indicate large influences of experimental factors and anesthetic events on these parameters. Immune cells and cytokine responses presented with distinct patterns for infants depending on age, birth location, and rearing conditions. Conclusions: Our results illustrate how the immune system changed over time and that there was variability among pediatric age groups. Reference ranges of results reported here will support interpretations for how infection and treatment may skew common immune correlates used for assessment of pathology or protection in research studies as well as help veterinarians in the clinical care of infant non-human primates. We highlighted the importance of using age-specific reference comparisons for pediatric studies and reiterated the utility of rhesus macaques as a model for human studies. Given the rapid transformation that occurs in multiple tissue compartments after birth and cumulative exposures to antigens as individuals grow, a better understanding of immunological development and how this relates to timing of infection or vaccination will support optimal experimental designs for developing vaccines and treatment interventions.

18.
EBioMedicine ; 18: 204-215, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28302457

RESUMO

Conventional HIV T cell vaccine strategies have not been successful in containing acute peak viremia, nor in providing long-term control. We immunized rhesus macaques intramuscularly and rectally using a heterologous adenovirus vectored SIV vaccine regimen encoding normally weakly immunogenic tat, vif, rev and vpr antigens fused to the MHC class II associated invariant chain. Immunizations induced broad T cell responses in all vaccinees. Following up to 10 repeated low-dose intrarectal challenges, vaccinees suppressed early viral replication (P=0.01) and prevented the peak viremia in 5/6 animals. Despite consistently undetectable viremia in 2 out of 6 vaccinees, all animals showed evidence of infection induced immune responses indicating that infection had taken place. Vaccinees, with and without detectable viremia better preserved their rectal CD4+ T cell population and had reduced immune hyperactivation as measured by naïve T cell depletion, Ki-67 and PD-1 expression on T cells. These results indicate that vaccination towards SIV accessory antigens vaccine can provide a level of acute control of SIV replication with a suggestion of beneficial immunological consequences in infected animals of unknown long-term significance. In conclusion, our studies demonstrate that a vaccine encoding subdominant antigens not normally associated with virus control can exert a significant impact on acute peak viremia.


Assuntos
Antígenos Heterófilos/imunologia , Vetores Genéticos/imunologia , Retrovirus dos Símios/fisiologia , Vacinas contra a SAIDS/imunologia , Adenoviridae/genética , Animais , Antígenos Heterófilos/genética , Antígenos Heterófilos/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Células HEK293 , Humanos , Macaca mulatta , Camundongos , Viremia/imunologia , Viremia/prevenção & controle , Replicação Viral/fisiologia
19.
JCI Insight ; 2(6): e91020, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28352660

RESUMO

Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197-specific neonatal CD4+ cells, activation of newborn and infant Streptococcus pneumoniae polysaccharide-specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10-100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development.


Assuntos
Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia , Adjuvantes Imunológicos/farmacologia , Adulto , Animais , Linfócitos B/imunologia , Células Cultivadas , Humanos , Recém-Nascido , Macaca mulatta , Linfócitos T/imunologia
20.
Cell Host Microbe ; 19(4): 529-40, 2016 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-27078070

RESUMO

The difficulty in detecting rare infected cells immediately after mucosal HIV transmission has hindered our understanding of the initial cells targeted by the virus. Working with the macaque simian immunodeficiency virus (SIV) vaginal challenge model, we developed methodology to identify discrete foci of SIV (mac239) infection 48 hr after vaginal inoculation. We find infectious foci throughout the reproductive tract, from labia to ovary. Phenotyping infected cells reveals that SIV has a significant bias for infection of CCR6+ CD4+ T cells. SIV-infected cells expressed the transcriptional regulator RORγt, confirming that the initial target cells are specifically of the Th17 lineage. Furthermore, we detect host responses to infection, as evidenced by apoptosis, cell lysis, and phagocytosis of infected cells. Thus, our analysis identifies Th17-lineage CCR6+ CD4+ T cells as primary targets of SIV during vaginal transmission. This opens new opportunities for interventions to protect these cells and prevent HIV transmission.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Células Th17/virologia , Vagina/virologia , Animais , Modelos Animais de Doenças , Feminino , Infecções por HIV/imunologia , Infecções por HIV/transmissão , Humanos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/genética , Células Th17/imunologia , Vagina/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA