Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.675
Filtrar
1.
Infect Genet Evol ; 88: 104684, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33352320

RESUMO

We document two cases of viremic and prolonged active infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) where the viral genome was conserved for two months, but infection was with little or no symptoms. The first infection persisted for 80 days and the second for 62 days. Clearance of infection occurred 40 and 41 days, respectively, after development of detectable antibodies. Both cases were identified incidentally in an investigation of reinfection in a cohort of 133,266 laboratory-confirmed infected persons.


Assuntos
Anticorpos Antivirais/sangue , Genoma Viral , RNA Viral/sangue , Viremia/imunologia , Adulto , Doenças Assintomáticas , /virologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Período de Incubação de Doenças Infecciosas , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , /imunologia , Fatores de Tempo , Viremia/diagnóstico , Viremia/virologia
2.
Transplant Proc ; 52(9): 2637-2641, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33012543

RESUMO

Here we report a single-center cohort of 6 patients (4 kidney only, and 2 simultaneous liver/kidney transplants) diagnosed with COVID-19 at a median of 1.9 years (range = 0.2-9.3 years) post transplant. Five (of 6) patients required inpatient admission, 2 patients (mortality = 33%) died. Among those with mortality, an increased concentration of inflammatory biomarkers (interleukin-6 and C-reactive protein) was noted with a lack of response to interleukin-6 blockade, remdesivir, and/or convalescent plasma. None of the kidney-only transplants (4/6; 67%) had elevation in plasma donor-derived cell-free DNA above the previously published cut-off of 1%, suggesting absence of significant allo-immune injury. Four (of 5) admitted patients had detectable SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) in blood on samples obtained at/during hospitalization. Of the 4 discharged patients, 2 patients with undetectable virus on repeat nasopharyngeal swabs had seroconversion with positive SARS-CoV-2 IgG formation at 30 to 48 days post infection. One patient had prolonged shedding of virus on nasopharyngeal swab at 28 days post discharge despite lack of symptoms. In this preliminary report, we find that immunocompromised transplant patients had higher rates of RNAemia (67%) than reported in the general population (15%), seeming absence of allo-immune injury despite systemic inflammation, and formation of IgG overtime after recovery from infection.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Hospedeiro Imunocomprometido/imunologia , Transplante de Rim/efeitos adversos , Pneumonia Viral/imunologia , Complicações Pós-Operatórias/imunologia , Adulto , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Imunização Passiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/virologia , Viremia/imunologia , Viremia/mortalidade , Viremia/virologia
3.
PLoS Pathog ; 16(9): e1008853, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886726

RESUMO

HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Efeito Fundador , Infecções por HIV , HIV-1/fisiologia , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana , Doença Aguda , Adolescente , Adulto , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Viremia/genética , Viremia/imunologia , Viremia/patologia , Replicação Viral/genética , Replicação Viral/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
4.
PLoS Comput Biol ; 16(8): e1008064, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817614

RESUMO

Antiretroviral therapy (ART) for HIV-1 infection is life-long. Stopping therapy typically leads to the reignition of infection and progressive disease. In a major breakthrough, recent studies have shown that early initiation of ART can lead to sustained post-treatment control of viremia, raising hopes of long-term HIV-1 remission. ART, however, elicits post-treatment control in a small fraction of individuals treated. Strikingly, passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 early in infection was found recently to elicit long-term control in a majority of SHIV-infected macaques, suggesting that HIV-1 remission may be more widely achievable. The mechanisms underlying the control elicited by bNAb therapy, however, remain unclear. Untreated infection typically leads to progressive disease. We hypothesized that viremic control represents an alternative but rarely realized outcome of the infection and that early bNAb therapy triggers a dynamical switch to this outcome. To test this hypothesis, we constructed a model of viral dynamics with bNAb therapy and applied it to analyse clinical data. The model fit quantitatively the complex longitudinal viral load data from macaques that achieved lasting control. The model predicted, consistently with our hypothesis, that the underlying system exhibited bistability, indicating two potential outcomes of infection. The first had high viremia, weak cytotoxic effector responses, and high effector exhaustion, marking progressive disease. The second had low viremia, strong effector responses, and low effector exhaustion, indicating lasting viremic control. Further, model predictions suggest that early bNAb therapy elicited lasting control via pleiotropic effects. bNAb therapy lowers viremia, which would also limit immune exhaustion. Simultaneously, it can improve effector stimulation via cross-presentation. Consequently, viremia may resurge post-therapy, but would encounter a primed effector population and eventually get controlled. ART suppresses viremia but does not enhance effector stimulation, explaining its limited ability to elicit post-treatment control relative to bNAb therapy.


Assuntos
Anticorpos Amplamente Neutralizantes/imunologia , Infecções por HIV/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Animais , Infecções por HIV/virologia , Humanos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Carga Viral , Viremia/imunologia
5.
Nature ; 585(7825): 414-419, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641828

RESUMO

Zika virus (ZIKV) belongs to the family Flaviviridae, and is related to other viruses that cause human diseases. Unlike other flaviviruses, ZIKV infection can cause congenital neurological disorders and replicates efficiently in reproductive tissues1-3. Here we show that the envelope protein (E) of ZIKV is polyubiquitinated by the E3 ubiquitin ligase TRIM7 through Lys63 (K63)-linked polyubiquitination. Accordingly, ZIKV replicates less efficiently in the brain and reproductive tissues of Trim7-/- mice. Ubiquitinated E is present on infectious virions of ZIKV when they are released from specific cell types, and enhances virus attachment and entry into cells. Specifically, K63-linked polyubiquitin chains directly interact with the TIM1 (also known as HAVCR1) receptor of host cells, which enhances virus entry in cells as well as in brain tissue in vivo. Recombinant ZIKV mutants that lack ubiquitination are attenuated in human cells and in wild-type mice, but not in live mosquitoes. Monoclonal antibodies against K63-linked polyubiquitin specifically neutralize ZIKV and reduce viraemia in mice. Our results demonstrate that the ubiquitination of ZIKV E is an important determinant of virus entry, tropism and pathogenesis.


Assuntos
Ubiquitinação , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus , Zika virus/metabolismo , Zika virus/patogenicidade , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Encéfalo/metabolismo , Linhagem Celular , Culicidae/citologia , Culicidae/virologia , Endossomos/metabolismo , Feminino , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Masculino , Fusão de Membrana , Camundongos , Especificidade de Órgãos , Poliubiquitina/imunologia , Poliubiquitina/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Tropismo Viral , Viremia/imunologia , Viremia/prevenção & controle , Viremia/virologia , Replicação Viral , Zika virus/química , Zika virus/genética , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia
6.
Transplant Proc ; 52(6): 1762-1768, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32611487

RESUMO

BACKGROUND: Prevention and early detection of BK polyomavirus (BKV) infection is important for long-term kidney graft survival; hence, pretransplant screening methods are essential to identify recipients at high risk for BKV infection. This study investigated the association of pretransplant donor and recipient BKV antibody status with the occurrence of post-transplant BKV infection. METHODS: We prospectively enrolled 47 adult living donor kidney transplant pairs from December 2014 to January 2016. Recipient and donor pretransplant BKV antibody titer was measured by hemagglutination inhibition (HI) test. Donor and recipient median HI titer of 1:20 was used as a cutoff to define seropositivity. Recipients were divided into 2 groups (BKV antibody donor-seropositive/recipient-seronegative (D+/R-) and non-D+/R-). Urinary cytology was used to screen for BKV infection. Plasma polymerase chain reaction testing for BKV DNA was used when decoy cells in urine were persistently detected. RESULTS: Nine (19.2%) of 47 patients belonged to the D+/R- group. Decoy cells were observed in 32 recipients (68.1%) during follow-up. BK viremia occurred in 3 (6.4%) cases. The maximum decoy cell count was significantly higher in the D+/R- group than in the non-D+/R- group (P = .0002). Decoy-cell-free survival was significantly shorter in the D+/R- group (P = .0220). Multivariate analysis identified only BKV antibody serostatus as an independent risk factor for decoy cell appearance (P = .0491). CONCLUSIONS: Pretransplant donor and recipient BKV antibody status was associated with higher maximum decoy cell count and shorter decoy-cell-free survival after kidney transplantation.


Assuntos
Anticorpos Antivirais/sangue , Vírus BK/imunologia , Complicações Pós-Operatórias/imunologia , Insuficiência Renal/sangue , Doadores de Tecidos/estatística & dados numéricos , Adulto , Anticorpos Antivirais/imunologia , Feminino , Humanos , Rim/imunologia , Rim/virologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/virologia , Período Pré-Operatório , Estudos Prospectivos , Insuficiência Renal/imunologia , Insuficiência Renal/cirurgia , Fatores de Risco , Transplantes/imunologia , Transplantes/virologia , Infecções Tumorais por Vírus/sangue , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Viremia/sangue , Viremia/imunologia , Viremia/virologia
7.
Int Immunopharmacol ; 85: 106683, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32531713

RESUMO

BACKGROUND: Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China. Our study aimed to evaluate the robustness of neutrophil to CD4+ lymphocyte ratio (NCD4LR) in predicting the negative conversion time (NCT) of SARS-CoV-2 in COVID-19 patients. METHODS: Univariate and multivariate analysis were conducted to evaluate the independency of NCD4LR in predicting NCT. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to assess the diagnostic accuracy. RESULTS: Compared with low NCD4LR patients, patients with high NCD4LR had an older age; higher incidence of fever, fatigue, chest distress/breath shortness, severer disease assessment on admission; higher levels of inflammatory indicators; low levels of lymphocyte subsets, and a longer NCT. Multivariate analysis also identified NCD4LR as an independent risk factor for delayed NCT. ROC analysis showed that NCD4LR had a better performance than neutrophil to lymphocyte ratio in predicting the virus negative conversion within 2 weeks (AUC = 0.772), 3 weeks (AUC = 0.710), 4 weeks (AUC = 0.728), or 5 weeks (AUC = 0.815). CONCLUSION: This study suggests that NCD4LR is a potential and useful biomarker for predicting the virus negative conversion time in COVID-19 patients. Furthermore, due to the NCDLR value is easily calculated, it can be widely used as a clinical biomarker for disease progression and clinical outcomes in COVID-19 patients.


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus/isolamento & purificação , Linfócitos T CD4-Positivos , Técnicas de Laboratório Clínico , Infecções por Coronavirus/imunologia , Contagem de Leucócitos , Neutrófilos , Pneumonia Viral/imunologia , Carga Viral , Viremia/imunologia , Adulto , Fatores Etários , Idoso , Área Sob a Curva , Betacoronavirus/imunologia , Biomarcadores , Convalescença , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Humanos , Inflamação , Pacientes Internados , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nasofaringe/virologia , Pandemias , Alta do Paciente , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Avaliação de Sintomas , Fatores de Tempo
8.
J Immunol ; 205(1): 12-19, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32423917

RESUMO

The 2019 coronavirus disease (COVID-19) pandemic caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created an unprecedented global crisis for the infrastructure sectors, including economic, political, healthcare, education, and research systems. Although over 90% of infected individuals are asymptomatic or manifest noncritical symptoms and will recover from the infection, those individuals presenting with critical symptoms are in urgent need of effective treatment options. Emerging data related to mechanism of severity and potential therapies for patients presenting with severe symptoms are scattered and therefore require a comprehensive analysis to focus research on developing effective therapeutics. A critical literature review suggests that the severity of SARS-CoV-2 infection is associated with dysregulation of inflammatory immune responses, which in turn inhibits the development of protective immunity to the infection. Therefore, the use of therapeutics that modulate inflammation without compromising the adaptive immune response could be the most effective therapeutic strategy.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Imunidade Adaptativa , Fatores Etários , Animais , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/patologia , Disparidades nos Níveis de Saúde , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Fatores Sexuais , Viremia/imunologia , Viremia/patologia
9.
Am J Trop Med Hyg ; 103(1): 112-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32431270

RESUMO

This study describes the natural history of dengue virus (DENV) infection in rhesus monkeys exposed to the bites of DENV-infected Aedes aegypti mosquitoes. Dengue virus-infected mosquitoes were generated by either intrathoracic inoculation or by oral feeding on viremic blood meals. Each of the six rhesus monkeys that were fed upon by intrathoracically infected mosquitoes developed non-structural protein 1 (NS1) antigenemia and an IgM response; viremia was detected in 4/6 individuals. No virological or immunological evidence of DENV infection was detected in the three monkeys exposed to mosquitoes that had been orally infected with DENV. These results demonstrate the utility of mosquito-borne challenge of rhesus monkeys with DENV.


Assuntos
Aedes/virologia , Anticorpos Antivirais/sangue , Vírus da Dengue/imunologia , Dengue/imunologia , Imunoglobulina M/sangue , Mosquitos Vetores/virologia , Viremia/imunologia , Animais , Dengue/sangue , Dengue/diagnóstico , Dengue/transmissão , Vírus da Dengue/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Macaca mulatta , Projetos Piloto , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas não Estruturais Virais/genética , Viremia/sangue , Viremia/diagnóstico , Viremia/transmissão
10.
Clin Immunol ; 215: 108410, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32276140

RESUMO

Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.


Assuntos
Infecções por Coronavirus/genética , Epigênese Genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Viremia/genética , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Antígeno CD11a/genética , Antígeno CD11a/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/imunologia , Metilação de DNA , Progressão da Doença , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Ligação Proteica , Receptores KIR/genética , Receptores KIR/imunologia , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Viremia/complicações , Viremia/epidemiologia , Viremia/imunologia
11.
BMC Med ; 18(1): 81, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32209092

RESUMO

INTRODUCTION: Immunological damage in acute HIV infection (AHI) may predispose to detrimental clinical sequela. However, studies on the earliest HIV-induced immunological changes are limited, particularly in sub-Saharan Africa. We assessed the plasma cytokines kinetics, and their associations with virological and immunological parameters, in a well-characterized AHI cohort where participants were diagnosed before peak viremia. METHODS: Blood cytokine levels were measured using Luminex and ELISA assays pre-infection, during the hyperacute infection phase (before or at peak viremia, 1-11 days after the first detection of viremia), after peak viremia (24-32 days), and during the early chronic phase (77-263 days). Gag-protease-driven replicative capacities of the transmitted/founder viruses were determined using a green fluorescent reporter T cell assay. Complete blood counts were determined before and immediately following AHI detection before ART initiation. RESULTS: Untreated AHI was associated with a cytokine storm of 12 out of the 33 cytokines analyzed. Initiation of ART during Fiebig stages I-II abrogated the cytokine storm. In untreated AHI, virus replicative capacity correlated positively with IP-10 (rho = 0.84, P < 0.001) and IFN-alpha (rho = 0.59, P = 0.045) and inversely with nadir CD4+ T cell counts (rho = - 0.58, P = 0.048). Hyperacute HIV infection before the initiation of ART was associated with a transient increase in monocytes (P < 0.001), decreased lymphocytes (P = 0.011) and eosinophils (P = 0.003) at Fiebig stages I-II, and decreased eosinophils (P < 0.001) and basophils (P = 0.007) at Fiebig stages III-V. Levels of CXCL13 during the untreated hyperacute phase correlated inversely with blood eosinophils (rho = - 0.89, P < 0.001), basophils (rho = - 0.87, P = 0.001) and lymphocytes (rho = - 0.81, P = 0.005), suggesting their trafficking into tissues. In early treated individuals, time to viral load suppression correlated positively with plasma CXCL13 at the early chronic phase (rho = 0.83, P = 0.042). CONCLUSION: While commencement of ART during Fiebig stages I-II of AHI abrogated the HIV-induced cytokine storm, significant depletions of eosinophils, basophils, and lymphocytes, as well as transient expansions of monocytes, were still observed in these individuals in the hyperacute phase before the initiation of ART, suggesting that even ART initiated during the onset of viremia does not abrogate all HIV-induced immune changes.


Assuntos
Citocinas/uso terapêutico , Infecções por HIV/imunologia , Carga Viral/métodos , Viremia/imunologia , Adolescente , Adulto , Citocinas/farmacologia , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Adulto Jovem
12.
Arch Virol ; 165(5): 1057-1067, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32144542

RESUMO

Human respiratory syncytial virus (hRSV) is the primary cause of severe respiratory tract disease in children and infants as well as in elderly and immunocompromised adults. The fusion protein (F) of hRSV is the major antigen eliciting a neutralizing antibody response and protective immunity in the host, especially those recognizing the prefusion F protein (pre-F). In this study, we made genetic constructs for expression of a recombinant prefusion F protein in Pichia pastoris GS115, called RGF. Using Escherichia coli BL21, we expressed the pre-F and postfusion F protein (Post-F), called RBF and Post-RBF, respectively. RGF and RBF showed high affinity for 5C4, a highly potent monoclonal antibody specific for pre-F. We studied the immunogenicity of RGF and RBF in mice. Compared to mice immunized with formalin-inactivated RSV (FI-RSV), mice immunized with RGF or RBF exhibited superior protective immunity, which was confirmed by serum neutralizing activity and viral clearance after challenge. As judged from the IgG1/IgG2a ratios and numbers of IFN-γ- and IL-4-secreting cells, RGF or RBF with alum adjuvant induced a balanced Th1-biased immune response and produced no signs of enhanced respiratory disease (ERD) upon hRSV challenge. In addition, the immunogenicity and protective efficacy of RGF were superior to those of RBF in mice. Therefore, RGF represents a potential vaccine candidate for the prevention of human infection with hRSV.


Assuntos
Proteínas Recombinantes/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Proteínas Virais de Fusão/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Antígenos Virais/genética , Antígenos Virais/imunologia , Modelos Animais de Doenças , Escherichia coli/genética , Escherichia coli/metabolismo , Camundongos , Pichia/genética , Pichia/metabolismo , Proteínas Recombinantes/genética , Infecções por Vírus Respiratório Sincicial/patologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/genética , Vacinas contra Vírus Sincicial Respiratório/isolamento & purificação , Células Th1/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/isolamento & purificação , Proteínas Virais de Fusão/genética , Viremia/imunologia
13.
Cytotherapy ; 22(3): 149-157, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32089448

RESUMO

Forkhead box P3 (FOXP3)+ regulatory T cell (Treg) reconstitution after unrelated donor umbilical cord blood transplantation in chemotherapy-naïve children is incompletely characterized. We studied 21 children with nonmalignant diseases receiving an identical alemtuzumab-containing regimen. We hypothesized that Treg recovery may be perturbed in patients not only by acute graft-versus-host disease (aGVHD) but also by viremia. Tregs and their memory and naïve subsets were serially monitored for proliferation and apoptosis along with conventional T cells (Tcon). A "reconstitution index" (RI) was calculated relative to pretransplantation values for each parameter. At 3 months post-UCBT, the RI of Tregs was faster compared with other immune components tested and was most rapid in patients free of aGVHD and viremia. There were significantly fewer Tregs in patients experiencing grade I-II aGVHD and/or viremia, leading to an imbalance between Tregs-Tcon ratios. Central and effector memory Tregs were most affected at this time point when they dominated in the circulation. Impaired Treg proliferation without increased apoptosis accounted for the reduced Treg-Tcon ratio. In patients affected with grade II aGVHD and viremia, the overall reduction in circulating Treg pool were associated with a more oligoclonal T-cell receptor ß repertoire. Taken together, aGVHD and viremia can lead to defective Treg expansion homeostasis.


Assuntos
Alemtuzumab/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Linfócitos T Reguladores/imunologia , Condicionamento Pré-Transplante , Viremia/imunologia , Adolescente , Proliferação de Células , Criança , Pré-Escolar , Feminino , Homeostase , Humanos , Lactente , Subpopulações de Linfócitos/imunologia , Masculino , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Viremia/patologia
14.
Sci Rep ; 10(1): 512, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949262

RESUMO

Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family that has been known to circulate for decades causing mild febrile illness. The more recent ZIKV outbreaks in the Americas and the Caribbean associated with congenital malformations and Guillain-Barré syndrome in adults have placed public health officials in high alert and highlight the significant impact of ZIKV on human health. New technologies to study the biology of ZIKV and to develop more effective prevention options are highly desired. In this study we demonstrate that direct delivery in mice of an infectious ZIKV cDNA clone allows the rescue of recombinant (r)ZIKV in vivo. A bacterial artificial chromosome containing the sequence of ZIKV strain Paraiba/2015 under the control of the cytomegalovirus promoter was complexed with a commercial transfection reagent and administrated using different routes in type-I interferon receptor deficient A129 mice. Clinical signs and death associated with ZIKV viremia were observed in mice. The rZIKV recovered from these mice remained fully virulent in a second passage in mice. Interestingly, infectious rZIKV was also recovered after intraperitoneal inoculation of the rZIKV cDNA in the absence of transfection reagent. Further expanding these studies, we demonstrate that a single intraperitoneal inoculation of a cDNA clone encoding an attenuated rZIKV was safe, highly immunogenic, and provided full protection against lethal ZIKV challenge. This novel in vivo reverse genetics method is a potentially suitable delivery platform for the study of wild-type and live-attenuated ZIKV devoid of confounding factors typical associated with in vitro systems. Moreover, our results open the possibility of employing similar in vivo reverse genetic approaches for the generation of other viruses and, therefore, change the way we will use reverse genetics in the future.


Assuntos
Cromossomos Artificiais Bacterianos/genética , DNA Complementar/genética , Vetores Genéticos/administração & dosagem , Viremia/prevenção & controle , Infecção por Zika virus/prevenção & controle , Zika virus/genética , Animais , Chlorocebus aethiops , DNA Complementar/imunologia , DNA Viral/genética , DNA Viral/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Receptor de Interferon alfa e beta/genética , Genética Reversa , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Células Vero , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Viremia/genética , Viremia/imunologia , Zika virus/imunologia , Infecção por Zika virus/genética , Infecção por Zika virus/imunologia
15.
Nat Commun ; 11(1): 272, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937782

RESUMO

Mucosa-associated invariant T (MAIT) cell loss in chronic HIV-1 infection is a significant insult to antimicrobial immune defenses. Here we investigate the response of MAIT cells during acute HIV-1 infection utilizing the RV217 cohort with paired longitudinal pre- and post-infection samples. MAIT cells are activated and expand in blood and mucosa coincident with peak HIV-1 viremia, in a manner associated with emerging microbial translocation. This is followed by a phase with elevated function as viral replication is controlled to a set-point level, and later by their functional decline at the onset of chronic infection. Interestingly, enhanced innate-like pathways and characteristics develop progressively in MAIT cells during infection, in parallel with TCR repertoire alterations. These findings delineate the dynamic MAIT cell response to acute HIV-1 infection, and show how the MAIT compartment initially responds and expands with enhanced function, followed by progressive reprogramming away from TCR-dependent antibacterial responses towards innate-like functionality.


Assuntos
Infecções por HIV/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Viremia/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Estudos de Coortes , HIV-1/fisiologia , Humanos , Imunidade Inata/genética , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Ativação Linfocitária , Células T Invariáveis Associadas à Mucosa/metabolismo , Células T Invariáveis Associadas à Mucosa/microbiologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transcriptoma
16.
Trop Anim Health Prod ; 52(4): 1725-1732, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31898019

RESUMO

Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) is characterized by high fever, respiratory distress, and high mortality in pigs of all ages and has severely affected the Vietnam pork industry in recent years. The study was conducted to compare the efficacy, safety, and overall performance of a modified live PRRSV-2 vaccine (Fostera PRRS) to an existing PRRSV modified live vaccine on a farm with a recent history of HP-PRRSV-associated respiratory diseases. A total of 351 pigs were randomly allocated to three treatment groups: (i) vaccinated with Fostera PRRS at 1 day of age (n = 118), (ii) vaccinated with Fostera PRRS (n = 118) at 21 days of age, and (iii) vaccinated with Amervac PRRS (n = 115) at 21 days of age. The Fostera PRRS vaccinated pigs had milder clinical symptoms, lower levels of HP-PRRSV viremia, fewer pathological changes in the lung, and higher body weight gain at the end of the study compared with the Amervac PRRS group. Vaccination of pigs with Fostera PRRS at 1 day of age also significantly reduced viral loads in their blood (P < 0.05) and induced higher anti-PRRSV antibody titers (P < 0.01) compared with pigs vaccinated with Amervac PRRS at 21 days of age. Fostera PRRS vaccination at 1 day of age can be useful in protecting young piglets from early HP-PRRSV infection because the immunized pigs were marketed 20 days earlier than their peers immunized at 21-day old as they reached the target market weight earlier in this study.


Assuntos
Anticorpos Antivirais/sangue , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vacinas Virais/imunologia , Animais , Síndrome Respiratória e Reprodutiva Suína/epidemiologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Suínos , Vacinação/veterinária , Vacinas Atenuadas/imunologia , Vietnã , Carga Viral , Viremia/imunologia
17.
Transplant Proc ; 52(1): 204-211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31889538

RESUMO

Cytomegalovirus (CMV) is the most common viral pathogen in kidney transplant recipients (KTRs), and CMV disease impacts patient and graft survivals. CMV-specific CD8 T cell mediated-immunity (CMI) may help to assess the risk of CMV disease and to adapt preventive treatment strategies. High-risk KTRs with CMV seropositive donors/seronegative recipients (D+/R-) were prospectively monitored after CMV prophylaxis discontinuation and during the first year post transplant for CMV viremia (World Health Organization standardization) and CMI (QuantiFERON-CMV). We analyzed the ability of CMI test to predict either subsequent spontaneous viral clearance or CMV disease after prophylaxis discontinuation in patients with asymptomatic viremia. We enrolled 12 consecutive (D+/R-) KTRs. Eleven patients developed a viremia during follow-up, but 7 of them (64%) exhibited a spontaneous viral clearance. At viremia onset, 6 of 11 patients (55%) had a positive CMI test, and all of them (6 of 6, 100%) had subsequent spontaneous viral clearance, compared with only 1 of 5 patients (20%) displaying a nonreactive CMI (P = .02). This latter patient exhibited a positive CMI test 15 days after viremia onset. Four of the 11 patients (36%) developed a CMV disease, and their CMI either remained nonreactive or became positive only after antiviral treatment. We conclude that D+/R- KTRs with asymptomatic viremia after prophylaxis discontinuation may benefit from QuantiFERON-CMV to predict when positive for the spontaneous viral clearance or when persistently negative or the development of a CMV disease.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/imunologia , Transplante de Rim , Viremia/diagnóstico , Adulto , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Feminino , Humanos , Imunidade Celular/imunologia , Masculino , Pessoa de Meia-Idade , Viremia/imunologia
18.
Transplant Proc ; 52(1): 97-101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31901328

RESUMO

BACKGROUND: In patients with hepatitis C virus (HCV) infection, the activation of the immune system by the virus or viral proteins leads to the production of numerous autoantibodies and clinical manifestations. The objectives of this study were to investigate the relationship between HCV and anti-HLA antibodies, as well as the effect of viremia on the antibody response and of direct-acting antivirals (DAAs) on anti-HLA antibody persistence in patients on the waiting list for a cadaveric kidney transplant. METHODS: A total of 395 patients from the cadaveric renal transplant waiting list were included in the study. The patients were grouped according to the presence of HCV infection, and patients with HCV positivity were further divided into a spontaneous clearance group and a persistent group. Anti-HLA antibodies were examined before and after treatment of the patients in the persistent group. The One Lambda Luminex method (Thermo Fisher Scientific, Waltham, MA, United States) was used to assess both HLA class I and II alleles and the anti-HLA antibody profile. RESULTS: Anti-HLA class I and II antibodies were detected in 48.2% and 55.1%, respectively, of the patients infected with HCV and in 21.8% and 20.4%, respectively, of the patients who were not infected. The level of anti-HLA A3, A11, B72, B52, Cw6, Cw16, DR3, and DQ4 antibodies was significantly higher in the patients infected with HCV. There was no statistically significant difference in class I and II antibody titration between the HCV-infected spontaneous clearance group and the persistent group (class I mean fluorescence intensity [MFI] ± SD: 13,583 ± 6224, 13,450 ± 9540, P = .808; Class II MFI ± SD: 13,000 ± 8673, 8440 ± 8302, P = .317, respectively). There was no significant difference in the class I and class II anti-HLA antibody profile and titration in the persistent group after treatment with DAAs (P > .05). CONCLUSIONS: The results of this study demonstrated that hepatitis C DAA treatment did not change the anti-HLA antibody profile and titration.


Assuntos
Antivirais/uso terapêutico , Autoanticorpos/efeitos dos fármacos , Hepacivirus/imunologia , Hepatite C Crônica/tratamento farmacológico , Transplante de Rim , Adulto , Antivirais/imunologia , Autoanticorpos/imunologia , Cadáver , Feminino , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Viremia/tratamento farmacológico , Viremia/imunologia , Viremia/virologia , Listas de Espera
20.
Int J Infect Dis ; 91: 210-217, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31821891

RESUMO

OBJECTIVES: Given the improvements in antiretroviral therapy (ART) in recent years, more pediatric HIV patients receiving ART are reaching adolescence and adulthood. This study investigated the influence of poor virological response (low-level viremia (LLV) and virological failure (VF)) on the immune system of these patients. METHODS: HIV-infected, ART-experienced pediatric patients (n=206) were enrolled in this cross-sectional study. The patients were subdivided into school-age children/early adolescents, middle adolescents, and late adolescents/young adults according to their age, and further classified into virological suppression (VS), LLV, and VF groups according to plasma viral load (pVL) measurement. Thymic output, T cells subsets, and immune activation were analyzed by flow cytometry. RESULTS: Compared with VS patients, VF patients displayed decreased CD4+ T cell counts, while LLV and VS patients had comparable CD4+ T cell counts regardless of age. Compared with VS patients, LLV and VF patients had higher percentages of CD8+HLA-DR+ and CD8+CD38high T cells, and the immune activation was positively correlated with pVL in VF and LLV patients. Thymic output levels (CD31+) and regulatory T cell subpopulations in LLV and VF patients were comparable to those in VS patients. LLV patients showed comparable percentages of T cell subsets (TN, TCM, TEMRA, and TEM) as VS patients in all age groups. CONCLUSIONS: LLV causes excessive immune activation although it does not impair T cell recovery or naïve-to-memory T cell conversion in pediatric patients living with HIV. Therefore, T cell immune activation should be monitored at the management of LLV during ART.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/imunologia , HIV-1 , Ativação Linfocitária , Linfócitos T/imunologia , Viremia/imunologia , Adolescente , Contagem de Linfócito CD4 , Criança , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Carga Viral , Viremia/tratamento farmacológico , Viremia/virologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA