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1.
Nat Immunol ; 15(1): 88-97, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24165795

RESUMO

The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.


Assuntos
Senescência Celular/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/genética , Fosfatidilinositol 3-Quinases/genética , Linfócitos T/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Diferenciação Celular/genética , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Genes Dominantes , Humanos , Immunoblotting , Síndromes de Imunodeficiência/tratamento farmacológico , Masculino , Linhagem , Fosfatidilinositol 3-Quinases/química , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Viremia/tratamento farmacológico , Viremia/genética , Viremia/virologia
2.
Kidney Int ; 106(3): 482-495, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38685562

RESUMO

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3+CD8midCD56+ NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection.


Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Células T Matadoras Naturais , Humanos , Transplante de Rim/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/sangue , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Células T Matadoras Naturais/imunologia , Citomegalovirus/imunologia , Citomegalovirus/isolamento & purificação , Citometria de Fluxo , Imunofenotipagem , Idoso , Imunidade Celular
3.
Antimicrob Agents Chemother ; 68(10): e0052524, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39291998

RESUMO

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration-time curve (AUC24h) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4-17.0) and weight of 28.2 kg (5.6-73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th-95th percentiles) steady state AUC24h with standard dosing was 38.3 mg/L·h (24.8-329.2) with 13 children having an AUC24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%-78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation.


Assuntos
Antivirais , Infecções por Citomegalovirus , Ganciclovir , Humanos , Criança , Ganciclovir/farmacocinética , Ganciclovir/administração & dosagem , Ganciclovir/sangue , Pré-Escolar , Lactente , Antivirais/farmacocinética , Antivirais/sangue , Antivirais/administração & dosagem , Masculino , Feminino , Adolescente , Estudos Retrospectivos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/virologia , Método de Monte Carlo , Área Sob a Curva , Monitoramento de Medicamentos/métodos , Hospedeiro Imunocomprometido
4.
J Med Virol ; 96(8): e29853, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39135474

RESUMO

This study aimed to retrospectively evaluate the baseline and follow-up viral loads and viral clearance times in cases followed for asymptomatic and symptomatic congenital cytomegalovirus (cCMV) infection between August 2010 and August 2022. Among 93 cases, they had asymptomatic (n: 55) and symptomatic (n: 38). The median baseline blood viral load detected in the symptomatic cCMV (ScCMV) infection (13 054 IU/mL) was significantly higher than that of asymptomatic cCMV (AcCMV) infection (4636 IU/mL) (p < 0.013). There was no difference in median viral clearance times (75 and 90 days, respectively) in baseline viremic cases in the ScCMV and AcCMV infection groups. There were no differences in median baseline blood viral load (6930 IU/mL and 14 268 IU/mL, respectively) and median viral clearance times (75 and 85 days, respectively) between the 6-week and 6-month antiviral treatment group. No correlation was found between baseline blood viral load, clinical severity, and the number of systems involved. However, in initial viremic cases, the viral load threshold for a symptomatic case was 8856 IU/mL, with 85.7% sensitivity and 54.5% specificity.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Carga Viral , Humanos , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/diagnóstico , Estudos Retrospectivos , Feminino , Masculino , Recém-Nascido , Citomegalovirus/isolamento & purificação , Citomegalovirus/genética , Infecções Assintomáticas , Lactente , Antivirais/uso terapêutico , Viremia/virologia
5.
J Med Virol ; 96(7): e29814, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39015038

RESUMO

Novel biomarkers reflecting the degree of immunosuppression in transplant patients are required to ensure eventual personalized equilibrium between rejection and infection risks. With the above aim, Torque Teno Virus (TTV) viremia was precisely examined in a large cohort of transplanted immunocompromised patients (192 hematological and 60 solid organ transplant recipients) being monitored for Cytomegalovirus reactivation. TTV load was measured in 2612 plasma samples from 448 patients. The results revealed a significant increase in TTV viral load approximately 14 days following CMV reactivation/infection in solid organ transplant (SOT) patients. No recognizable difference in TTV load was noted among hematological patients during the entire timeframe analyzed. Furthermore, a temporal gap of approximately 30 days was noted between the viral load peaks reached by the two viruses, with Cytomegalovirus (CMV) preceding TTV. It was not possible to establish a correlation between CMV reactivation/infection and TTV viremia in hematological patients. On the other hand, the SOT patient cohort allowed us to analyze viral kinetics and draw intriguing conclusions. Taken together, the data suggest, to our knowledge for the first time, that CMV infection itself could potentially cause an increase in TTV load in the peripheral blood of patients undergoing immunosuppressive therapy.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Infecções por Vírus de DNA , Hospedeiro Imunocomprometido , Torque teno virus , Carga Viral , Viremia , Humanos , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Masculino , Infecções por Vírus de DNA/virologia , Infecções por Vírus de DNA/sangue , Infecções por Vírus de DNA/imunologia , Pessoa de Meia-Idade , Feminino , Adulto , Terapia de Imunossupressão/efeitos adversos , Ativação Viral , Transplantados/estatística & dados numéricos , Idoso , Estudos de Coortes
6.
Mult Scler ; 30(11-12): 1445-1454, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39246021

RESUMO

BACKGROUND: Infection by cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) play a prognostic role in multiple sclerosis (MS). OBJECTIVES: To explore whether humoral immune responses to HCMV and EBV at disease onset were associated with changes in serum and cerebrospinal fluid (CSF) levels of inflammatory and neurodegeneration biomarkers. METHODS: Ninety-eight MS patients with a median follow-up of 20 years were included in the study. The levels of a panel of nine biomarkers were measured in serum (N = 60) and CSF (N = 61) samples of patients at the time of the first demyelinating event. RESULTS: Immune responses to HCMV inversely correlated with serum neurofilament light chain (sNfL) levels (rho = -0.367; p = 0.039). sNfL levels were reduced in patients with high immune responses to HCMV (p = 0.006). Elevated sNfL levels were associated with higher risk of Expanded Disability Status Scale (EDSS) 3.0 (p = 0.016), 4.0 (p = 0.009) and 6.0 (p = 0.003), and with higher risk of developing secondary progressive MS (p = 0.003) and to receive treatment (p = 0.032). Serum soluble CD21 levels were increased in patients with high immune responses to EBV nuclear antigen 1 (p = 0.020). CONCLUSIONS: High immune responses to HCMV are associated with limited disease progression and central nervous system (CNS) injury in MS patients. These findings reinforce the protective role of HCMV infection in MS.


Assuntos
Biomarcadores , Infecções por Citomegalovirus , Citomegalovirus , Proteínas de Neurofilamentos , Humanos , Masculino , Feminino , Adulto , Proteínas de Neurofilamentos/sangue , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/complicações , Pessoa de Meia-Idade , Biomarcadores/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/sangue , Herpesvirus Humano 4/imunologia , Progressão da Doença , Avaliação da Deficiência , Seguimentos , Adulto Jovem
7.
Eur J Clin Microbiol Infect Dis ; 43(10): 1883-1897, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39066967

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infection is widely prevalent worldwide, which may have relationship with dyslipidemia. The aim of this study is to explore the association between CMV infection and dyslipidemia. METHODS: The total observed population of this study included 14,163 participants aged 6-49 years from 1999 to 2004 National Health and Nutritional Examination Surveys (NHANES). Immunoglobulin G (IgG) levels and four lipid parameters (triglyceride, low density lipoprotein-cholesterol (LDL-C), total cholesterol, and high density lipoprotein-cholesterol (HDL-C)) were analyzed by performing multiple logistic regression and subgroup analysis. RESULTS: The median values of triglycerides, LDL-C and total cholesterol levels in the CMV positive group were higher than those in CMV negative group while a lower median value of HDL-C existed in positive group. After controlling for potential confounders (sex, age, race, country of birth, education, poverty-to-income ratio(PIR)), a close association between CMV infection and low HDL-C was observed, which persisted in the men aged 30-49 and women aged 12-19, 30-49. CONCLUSIONS: CMV infection is related to dyslipidemia, and this association is more significant in the serum HDL-C. Further cohort studies and experimental evidences can be conducted to test this association and then guide clinical practice.


Assuntos
Infecções por Citomegalovirus , Dislipidemias , Inquéritos Nutricionais , Humanos , Dislipidemias/epidemiologia , Dislipidemias/sangue , Masculino , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/sangue , Feminino , Adolescente , Pessoa de Meia-Idade , Adulto , Criança , Adulto Jovem , Estados Unidos/epidemiologia , Triglicerídeos/sangue , HDL-Colesterol/sangue , Imunoglobulina G/sangue , Citomegalovirus
8.
New Microbiol ; 47(1): 52-59, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38700884

RESUMO

Monitoring Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection after transplantation is recommended to enable preemptive therapy. However, the most suitable sample type remains unclear. Patients who underwent hematopoietic stem cell or liver transplantation were included in this study. Viral loads in sequential whole-blood and plasma samples were retrospectively analyzed. EBV DNA was detected more frequently in whole blood (55%) than in plasma (18%). The detection rate of CMV DNA was similar between the two sample types. The correlation of viral loads between the two sample types were 0.515 and 0.688 for EBV and CMV, respectively. Among paired samples in which EBV DNA was detected in whole blood, the plasma EBV detection rate was significantly higher in patients who underwent hematopoietic stem cell transplantation than in those who underwent liver transplantation. The viral DNA load in whole blood and plasma showed similar trends. The EBV detection rate was higher in whole blood, and a high correlation was observed between CMV DNA loads and whole blood and plasma. These results indicate that whole blood is more sensitive for monitoring both EBV and CMV, whereas plasma is a potential alternative sample for monitoring CMV.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Carga Viral , Humanos , Citomegalovirus/genética , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/diagnóstico , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , DNA Viral/sangue , Adulto Jovem , Transplante de Células-Tronco Hematopoéticas , Idoso , Plasma/virologia , Transplante de Fígado , Adolescente
9.
Int J Mol Sci ; 25(16)2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39201447

RESUMO

Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are antiviral medications primarily used to treat infections caused by cytomegalovirus (CMV), particularly in immunocompromised individuals such as solid organ transplant (SOT) recipients. Therapy with GCV is associated with significant side effects, including bone marrow suppression. Therefore, therapeutic drug monitoring (TDM) is mandatory for an appropriate balance between subtherapeutic and toxic drug levels. This study aimed to develop and validate three novel methods based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for GCV determination in serum (reference methodology), dried serum spots (DSS), and VAMS-Mitra™ devices. The methods were optimized and validated in the 0.1-25 mg/L calibration range. The obtained results fulfilled the EMA acceptance criteria for bioanalytical method validation. Assessment of DSS and VAMS techniques extended GCV stability to serum for up to a minimum of 49 days (at room temperature, with desiccant). Developed methods were effectively evaluated using 80 clinical serum samples from pediatric renal transplant recipients. Obtained samples were used for DSS, and dried serum VAMS samples were manually generated in the laboratory. The results of GCV determination using serum-, DSS- and VAMS-LC-MS/MS methods were compared using regression analysis and bias evaluation. The conducted statistical analysis confirmed the interchangeability between developed assays. The DSS and VAMS samples are more accessible and stable during storage, transport and shipment than classic serum samples.


Assuntos
Antivirais , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos , Ganciclovir , Espectrometria de Massas em Tandem , Humanos , Monitoramento de Medicamentos/métodos , Teste em Amostras de Sangue Seco/métodos , Espectrometria de Massas em Tandem/métodos , Ganciclovir/análogos & derivados , Ganciclovir/sangue , Ganciclovir/uso terapêutico , Antivirais/sangue , Antivirais/uso terapêutico , Cromatografia Líquida/métodos , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/tratamento farmacológico , Valganciclovir/uso terapêutico , Valganciclovir/sangue , Criança
10.
J Immunol ; 206(5): 1027-1038, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33483348

RESUMO

Alterations in the γδ T cell compartment have been reported in immunocompromised individuals infected with hepatitis E virus (HEV)-g3. We now report the analysis of blood γδ T cells from acutely HEV-infected individuals in the absence of immunosuppression. In these patients, non-Vδ2 (ND2) γδ T cells outnumbered otherwise predominant Vδ2 cells selectively in human CMV (HCMV)-seropositive patients and were higher than in HCMVpos controls, mimicking HCMV reactivation, whereas their serum was PCR-negative for HCMV. Stimulation of their lymphocytes with HEV-infected hepatocarcinoma cells led to an HEV-specific response in γδ subsets of HCMVpos individuals. HEV infection was associated with a lowered expression of TIGIT, LAG-3, and CD160 immune checkpoint markers on ND2 effector memory cells in HCMVneg but not in HCMVpos HEV patients. γδ cell lines, predominantly ND2, were generated from patients after coculture with hepatocarcinoma cells permissive to HEV and IL-2/12/18. Upon restimulation with HEV-infected or uninfected cells and selected cytokines, these cell lines produced IFN-γ and IL-10, the latter being induced by IL-12 in IFN-γ-producing cells and upregulated by HEV and IL-18. They were also capable of suppressing the proliferation of CD3/CD28-activated CD4 cells in transwell experiments. Importantly, IL-10 was detected in the plasma of 10 of 10 HCMVpos HEV patients but rarely in controls or HCMVneg HEV patients, implying that γδ cells are probably involved in IL-10 production at the acute phase of infection. Our data indicate that HEV mobilizes a pool of ND2 memory cells in HCMV carriers, promoting the development of an immunoregulatory environment.


Assuntos
Infecções por Citomegalovirus/imunologia , Hepatite E/imunologia , Interleucina-10/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular Tumoral , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/virologia , Células Hep G2 , Hepatite E/sangue , Hepatite E/virologia , Vírus da Hepatite E/imunologia , Humanos , Memória Imunológica/imunologia
11.
BJOG ; 129(2): 301-312, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34651405

RESUMO

OBJECTIVE: To assess the cost-effectiveness of prenatal detection of congenital cytomegalovirus (cCMV) following maternal primary infection in the first trimester within standard pregnancy follow-up or involving population-based screening (serological testing at 7 and 12 weeks of gestation), with or without secondary prevention (valaciclovir) in maternal CMV primary infection. DESIGN: Cost-effectiveness study from the perspective of the French national health insurance system. SETTING: Cost-effectiveness based on previously published probability estimates and associated plausible ranges hypothetical population of 1,000,000 pregnant women. POPULATION: Hypothetical population of 1,000,000 pregnant women. METHODS: Cost-effectiveness of detecting fetal cCMV in terms of the total direct medical costs involved and associated expected outcomes. MAIN OUTCOME MEASURES: Detection rates and clinical outcomes at birth. RESULTS: Moving to a population-based approach for targeting fetal CMV infections would generate high monetary and organizational costs while increasing detection rates from 15% to 94%. This resource allocation would help implementing horizontal equity according to which individuals with similar medical needs should be treated equally. Secondary prevention with valaciclovir had a significant effect on maternal-fetal CMV transmission and clinical outcomes in newborns, with a 58% decrease of severely infected newborns for a 3.5% additional total costs. Accounting for women decision-making (amniocentesis uptake and termination of pregnancy in severe cases) did not impact the cost-effectiveness results. CONCLUSIONS: These findings could fuel thinking on the opportunity of developing clinical guidelines to rule identification of cCMV infection and administration of in-utero treatment. These findings could fuel the development of clinical guidelines on the identification of congenital CMV infection and the administration of treatment in utero. TWEETABLE ABSTRACT: CMV serological screening followed by valaciclovir prevention may prevent 58% to 71% of severe cCMV cases for 38 € per pregnancy.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Complicações Infecciosas na Gravidez/diagnóstico , Diagnóstico Pré-Natal , Análise Custo-Benefício , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/economia , Feminino , França , Humanos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Programas Nacionais de Saúde , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/economia , Primeiro Trimestre da Gravidez
12.
J Clin Lab Anal ; 36(1): e24131, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34811823

RESUMO

BACKGROUND: The aim of this study was to evaluate the predictive value of the hematological parameters in the identification of human cytomegalovirus (CMV) infection in infants less than 3 months. METHODS: A single-center, observational study of infants with CMV infection was conducted retrospectively. Routine blood parameters were analyzed in CMV-infected infants and controls with no differences of birthweight, sex, gestational age at birth, and date of admission. Furthermore, receiver-operating curve was used to assess the predictive value of the hematological parameters for CMV infection. RESULTS: One hundred ninety cases with CMV infection were studied retrospectively. Compared with the control group, there were significant differences in the white blood cell count, neutrophil count, lymphocyte count, platelet count, hemoglobin, neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and lymphocyte-to-monocyte (LMR) for the patients with CMV infection (all p < 0.001). The best predicted values for CMV infection based on the area under the curve (AUC) were NLR and PLR with the optimal cut-off value of 0.28 and 65.36. NLR-PLR score of 0, 1, or 2 based on an elevated NLR (>0.28), an elevated PLR (>65.36), or both. NLR-PLR score for CMV infection prediction yielded higher AUC values than NLR or PLR alone (0.760 vs. 0.689, 0.689; p < 0.001). CONCLUSIONS: The NLR combined with PLR is potentially useful as a predictor of CMV infection in infants less than 3 months.


Assuntos
Contagem de Células Sanguíneas/estatística & dados numéricos , Infecções por Citomegalovirus , Biomarcadores , Pré-Escolar , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/epidemiologia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
13.
Proc Natl Acad Sci U S A ; 116(26): 13036-13041, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31189602

RESUMO

Human cytomegalovirus (HCMV) causes severe disease in infants and immunocompromised people. There is no approved HCMV vaccine, and vaccine development strategies are complicated by evidence of both persistent infection and reinfection of people with prior immunity. The greatest emphasis has been placed on reducing transmission to seronegative pregnant women to prevent vertical transmission and its potentially severe sequelae. Increasing evidence suggests that the earliest host-HCMV interactions establish conditions for viral persistence, including evasion of host immune responses to the virus. Using a nonhuman primate model of HCMV infection, we show that rhesus macaques immunized against viral interleukin-10 (IL-10) manifest delayed rhesus cytomegalovirus (RhCMV) acquisition and altered immune responses to the infection when it does occur. Among animals with the greatest antiviral IL-10-neutralizing activity, the timing of RhCMV seroconversion was delayed by an average of 12 weeks. After acquisition, such animals displayed an antibody response to the new infection, which peaked as expected after 2 weeks but then declined rapidly. In contrast, surprisingly, vaccination with glycoprotein B (gB) protein had no discernible impact on these outcomes. Our results demonstrate that viral IL-10 is a key regulator of successful host immune responses to RhCMV. Viral IL-10 is, therefore, an important target for vaccine strategies against cytomegalovirus (CMV). Furthermore, given the immunoregulatory function of viral IL-10, targeting this protein may prove synergistic with other vaccine therapies and targets. Our study also provides additional evidence that the earliest host-CMV interactions can have a significant impact on the nature of persistent infection.


Assuntos
Antígenos Virais/imunologia , Infecções por Citomegalovirus/prevenção & controle , Vacinas contra Citomegalovirus/farmacologia , Citomegalovirus/imunologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Interleucina-10/imunologia , Proteínas do Envelope Viral/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antígenos Virais/administração & dosagem , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/transmissão , Infecções por Citomegalovirus/virologia , Vacinas contra Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/uso terapêutico , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade nas Mucosas , Imunogenicidade da Vacina , Interleucina-10/administração & dosagem , Macaca mulatta , Gravidez , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas do Envelope Viral/administração & dosagem , Eliminação de Partículas Virais/imunologia
14.
Immunology ; 162(3): 314-327, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33283275

RESUMO

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that is potentially pathogenic in immunosuppressed individuals and pregnant females during primary infection. The HCMV envelope glycoprotein B (gB) facilitates viral entry into all cell types and induces a potent immune response. AD-2 epitope is a highly conserved linear neutralizing epitope of gB and a critical target for antibodies; however, only 50% of sero-positive individuals make IgG antibodies to this site and IgA responses have not been fully investigated. This study aimed to compare IgG and IgA responses against gB and the AD-2 epitope in naturally exposed individuals and those receiving a recombinant gB/MF59 adjuvant vaccine. Thus, vaccination of sero-positive individuals improved pre-existing gB-specific IgA and IgG levels and induced de novo gB-specific IgA and IgG responses in sero-negative recipients. Pre-existing AD-2 IgG and IgA responses were boosted with vaccination, but de novo AD-2 responses were not detected. Naturally exposed individuals had dominant IgG responses towards gB and AD-2 compared with weaker and variable IgA responses, although a significant IgA binding response to AD-2 was observed within human breastmilk samples. All antibodies binding AD-2 contained kappa light chains, whereas balanced kappa/lambda light chain usage was found for those binding to gB. V region-matched AD-2-specific recombinant IgG and IgA bound both to gB and to AD-2 and neutralized HCMV infection in vitro. Overall, these results indicate that although human IgG responses dominate, IgA class antibodies against AD-2 are a significant component of human milk, which may function to protect neonates from HCMV.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/imunologia , Epitopos , Imunogenicidade da Vacina , Imunoglobulina A/sangue , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Animais , Especificidade de Anticorpos , Sítios de Ligação de Anticorpos , Linhagem Celular Tumoral , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Células HEK293 , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Leite Humano/imunologia , Leite Humano/virologia , Polissorbatos/administração & dosagem , Ligação Proteica , Esqualeno/administração & dosagem , Vacinação , Proteínas do Envelope Viral/metabolismo , Vacinas Virais/imunologia
15.
Clin Immunol ; 227: 108727, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887436

RESUMO

With the global spread of coronavirus disease 2019 (COVID-19), the important role of natural killer (NK) cells in the control of various viral infections attracted more interest, via non-specific activation, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and activating receptors, as well as specific activation, such as memory-like NK generation. In response to different viral infections, NK cells fight viruses in different ways, and different NK subsets proliferate. For instance, cytomegalovirus (CMV) induces NKG2C + CD57 + KIR+ NK cells to expand 3-6 months after hematopoietic stem cell transplantation (HSCT), but human immunodeficiency virus (HIV) induces KIR3DS1+/KIR3DL1 NK cells to expand in the acute phase of infection. However, the similarities and differences among these processes and their molecular mechanisms have not been fully discussed. In this article, we provide a summary and comparison of antiviral mechanisms, unique subset expansion and time periods in peripheral blood and tissues under different conditions of CMV, HIV, Epstein-Barr virus (EBV), COVID-19 and hepatitis B virus (HBV) infections. Accordingly, we also discuss current clinical NK-associated antiviral applications, including cell therapy and NK-related biological agents, and we state the progress and future prospects of NK cell antiviral treatment.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Interações entre Hospedeiro e Microrganismos/imunologia , Células Matadoras Naturais/imunologia , Citotoxicidade Celular Dependente de Anticorpos , COVID-19/sangue , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , HIV/imunologia , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , Hepatite B/sangue , Hepatite B/imunologia , Hepatite B/virologia , Vírus da Hepatite B/imunologia , Herpesvirus Humano 4/imunologia , Humanos , SARS-CoV-2/imunologia , Receptores Toll-Like/metabolismo
16.
J Med Virol ; 93(8): 5017-5024, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33629381

RESUMO

An abdominal aortic aneurysm (AAA) is a multifactorial disease with a variety of genetic and environmental risk factors, but the exact mechanism of AAA formation and progression is still not well understood. The present study investigated the frequency of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and papillomavirus types 6 and 11 (HPV6 and HPV11), their impact on clinical manifestations of cardiovascular diseases, and their possible association with inflammation in patients with AAA and healthy volunteers. Genotyping of CMV UL75, EBV LMP-1, and HPV6, and HPV11 E6 was performed by polymerase chain reaction (PCR), while the viral DNA loads were measured by quantitative real-time PCR. Cytokine levels were determined by enzyme-linked immunosorbent assays. The CMV UL75 was detected more frequently in the blood of patients with AAA than in the blood of healthy volunteers (32.7% vs. 6.3%, p < .0001). Neither EBV LMP-1 nor HPV6 E6 was found in blood and aortic wall biopsies, while the HPV11 E6 was detected in 36.4% of AAA walls. The CMV infection in patients with AAA was associated with an increased risk of hypertension and coronary artery disease (OR, 9.057; 95% CI, 1.141-71.862; p = .037; and OR, 2.575; 95% CI, 1.002-6.615; p = .049, respectively). Additionally, CMV-infected patients with AAA had higher tumor necrosis factor-α levels compared with noninfected subjects (p = .017). Our findings suggest that CMV infection can stimulate local inflammation in the aorta but is not a direct cause of most abdominal aortic aneurysms.


Assuntos
Aneurisma da Aorta Abdominal/virologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/isolamento & purificação , Idoso , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Citomegalovirus/genética , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/patologia , Feminino , Genótipo , Herpesviridae/genética , Herpesviridae/isolamento & purificação , Infecções por Herpesviridae/sangue , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Humanos , Hipertensão/sangue , Hipertensão/patologia , Hipertensão/virologia , Masculino , Pessoa de Meia-Idade , Risco , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
17.
J Med Virol ; 93(11): 6301-6308, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34076905

RESUMO

Human cytomegalovirus (HCMV) is a common cause of significant morbidity and mortality in transplant recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We evaluated interferon-γ (IFN-γ) secretion by HCMV NLV-specific CD8+ T cells in HCMV-reactivated allo-HSCT recipients using an enzyme-linked immunospot (ELISPOT) assay at 3 months post-transplantation. Blood samples from 47 recipients were tested for HCMV DNAemia, HCMV pp65 antigenemia, and anti-HCMV immunoglobulins (IgG/IgM) over 3 months post-transplantation. Of the 47 transplant recipients, 26 were HLA-A*02 positive and 21 were HLA-A*02 negative. The results were essentially consistent between the 47 transplant recipients and the HLA-A*02-positive recipients. HCMV DNAemia was not linearly correlated with IFN-γ spot-forming cells (SFCs) counts; IFN-γ SFCs counts did not differ significantly between the HCMV DNAemia-positive and -negative groups, whereas the HCMV-DNA virus loads were inversely correlated with the IFN-γ SFCs counts. HCMV pp65 antigenemia was not linearly correlated with IFN-γ SFCs counts; IFN-γ SFCs counts in the HCMV pp65 antigenemia-positive and -negative groups were similar. More IFN-γ SFCs counts were detected in transplant recipients with high anti-HCMV-IgG antibody titers than in those with low anti-HCMV-IgG titers pre-transplantation in the 47 recipients. Anti-HCMV-IgG antibody titers were positively linearly correlated with IFN-γ SFCs counts in HLA-A*02-positive recipients. The HCMV infection indicators used to monitor HCMV reactivation had different values in transplant recipients. The use of the IFN-γ SFCs counts measured by ELISPOT to evaluate the risk of HCMV reactivation needs further study.


Assuntos
Infecções por Citomegalovirus/diagnóstico , ELISPOT/métodos , ELISPOT/normas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interferon gama/análise , Infecção Latente/diagnóstico , Transplantados/estatística & dados numéricos , Adolescente , Adulto , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Interferon gama/imunologia , Infecção Latente/sangue , Infecção Latente/imunologia , Infecção Latente/virologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Cytokine ; 143: 155547, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33931289

RESUMO

Persistent inflammation, despite anti-retroviral therapy (ART), is an independent predictor of mortality and comorbidities in HIV infection. Multiple factors, including lifestyle and chronic viral coinfections, may contribute. Several of these factors are also associated with a chronic inflammation in the general population. Little is known about the degree to which these factors influence inflammation in HIV infection, particularly within the first year of ART. The purpose of this study was to distinguish the effects of factors (gender, body mass index, cholesterol and triglyceride levels, smoke habit and cytomegalovirus seropositivity), known to contribute to inflammation, on inflammation biomarkers over the first year of ART in HIV-infected patients. Linear mixed model analysis revealed significant biomarker decreases [soluble CD14 (s-CD14), soluble CD163 (s-CD163) and D-dimer (DD)], or increases [C Reactive Protein (CRP) and interleukin-6 (IL-6)] over time in the whole cohort, differences in most categories (genders for IL-6, smoke habit for s-CD14, cytomegalovirus infection for s-CD163 and IL-6) and in some category × time interactions [gender for interleukin-7 (IL-7)], cytomegalovirus infection for s-CD14 and cholesterol levels for s-CD14 and Tumor Necrosis Factor α (TNF-α)]. This explorative longitudinal study suggests further investigations on targeting inflammation pathophysiology in HIV-infected patients on ART.


Assuntos
Terapia Antirretroviral de Alta Atividade , Índice de Massa Corporal , Infecções por Citomegalovirus/sangue , Infecções por HIV/tratamento farmacológico , Inflamação/sangue , Lipídeos/sangue , Caracteres Sexuais , Fumar/sangue , Adulto , Idoso , Biomarcadores/sangue , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , Hábitos , Humanos , Masculino , Pessoa de Meia-Idade
19.
Virol J ; 18(1): 30, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514390

RESUMO

INTRODUCTION: Despite being a leading infectious cause of childhood disability globally, testing for cytomegalovirus (CMV) infections in pregnancy is generally not done in Sub-Sahara Africa (SSA), where breastfeeding practice is almost universal. Whilst CMV and human immunodeficiency virus (HIV) are both endemic in SSA, the relationship between antenatal plasma CMV-DNA, HIV-1-RNA levels and HIV-1-mother to child transmission (MTCT) including pregnancy outcomes remains poorly described. METHODS: Pregnant women at least 20 weeks' gestational age at enrolment were recruited from relatively poor high-density suburbs in Harare, Zimbabwe. Mother-infant dyads were followed up until 6 months postpartum. In a case-control study design, we tested antenatal plasma CMV-DNA levels in all 11 HIV-1 transmitting mothers, as well as randomly selected HIV-infected but non-transmitting mothers and HIV-uninfected controls. CMV-DNA was detected and quantified using polymerase chain reaction (PCR) technique. Antenatal plasma HIV-1-RNA load was quantified by reverse transcriptase PCR. Infants' HIV-1 infection was detected using qualitative proviral DNA-PCR. Predictive value of antenatal plasma CMV-DNAemia (CMV-DNA of > 50 copies/mL) for HIV-1-MTCT was analyzed in univariate and multivariate regression analyses. Associations of CMV-DNAemia with HIV-1-RNA levels and pregnancy outcomes were also explored. RESULTS: CMV-DNAemia data were available for 11 HIV-1 transmitting mothers, 120 HIV-infected but non-transmitting controls and 46 HIV-uninfected mothers. In a multivariate logistic regression model, we found a significant association between CMV-DNAemia of > 50 copies/mL and HIV-1 vertical transmission (p = 0.035). There was no difference in frequencies of detectable CMV-DNAemia between HIV-infected and -uninfected pregnant women (p = 0.841). However, CMV-DNA levels were higher in immunosuppressed HIV-infected pregnant women, CD4 < 200 cells/µL (p = 0.018). Non-significant associations of more preterm births (< 37 weeks, p = 0.063), and generally lower birth weights (< 2500 g, p = 0.450) were observed in infants born of HIV-infected mothers with CMV-DNAemia. Furthermore, in a multivariate analysis of HIV-infected but non-transmitting mothers, CMV-DNAemia of > 50 copies/mL correlated significantly with antenatal plasma HIV-1-RNA load (p = 0.002). CONCLUSION: Antenatal plasma CMV-DNA of > 50 copies/mL may be an independent risk factor for HIV-1-MTCT and higher plasma HIV-1-RNA load, raising the possibility that controlling antenatal CMV-DNAemia might improve infant health outcomes. Further studies with larger sample sizes are warranted to confirm our findings.


Assuntos
Infecções por Citomegalovirus/sangue , Citomegalovirus/genética , DNA Viral/sangue , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Adolescente , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , HIV-1/genética , Humanos , Lactente , Recém-Nascido , Mães , Gravidez , Complicações Infecciosas na Gravidez/virologia , Resultado da Gravidez , Diagnóstico Pré-Natal/estatística & dados numéricos , Adulto Jovem , Zimbábue
20.
Gynecol Oncol ; 160(1): 193-198, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33168306

RESUMO

OBJECTIVES: Cytomegalovirus (CMV) is a common infection that establishes latency in healthy people. CMV has been associated with alterations of the immune compartment leading to improved responses, while inflammation has been shown to adversely impact outcomes. We investigated whether CMV serostatus predicts outcomes in ovarian cancer in the presence or absence of inflammation. METHODS: A total of 106 patients with serous ovarian cancer from 2006 to 2009 were analyzed. CMV and systemic inflammation was measured using CMV immunoglobulin G (IgG) and C-reactive protein (CRP), respectively, in serum collected prior to cytoreduction. Patients were stratified by CMV IgG (non-reactive, reactive/borderline) and CRP (≤10, >10 mg/L) status. Overall survival (OS) and recurrence-free survival (RFS) were compared by group using log-rank tests and Cox proportional hazards regression models adjusting for age at surgery. RESULTS: Of 106 eligible patients, 40 (37.7%) were CMV+/CRP+, 24 (22.6%) CMV+/CRP-, 19 (17.9%) CMV-/CRP+, and 23 (21.7%) CMV-/CRP-. CRP+ had higher CA-125 levels (P = 0.05) and higher rates of suboptimal debulking (P = 0.03). There were no other significant differences in demographic, surgical, or pathologic factors between groups. CMV+/CRP+ patients median RFS and OS were 16.9 months (95% CI: 9.0-21.1) and 31.7 months (95% CI: 25.0-48.7), respectively, with a significantly worse RFS (aHR: 1.85, 95% CI: 1.05-3.24, P = 0.03) and OS (aHR: 2.12, 95% CI: 1.17-3.82, P = 0.01) compared to CMV-/CRP- (RFS = 31.2 months (95% CI: 16.0-56.4) and OS = 63.8 months (95% CI: 50.7-87.0)). CMV+/CRP- group displayed the longest OS (89.3 months). CONCLUSIONS: Previous exposure to CMV and high CRP at surgery portended worse RFS and OS compared to women who tested negative. The CMV+/CRP- group had the longest OS, indicating that CMV status alone, in the absence of inflammation, may be protective.


Assuntos
Cistadenocarcinoma Seroso/cirurgia , Cistadenocarcinoma Seroso/virologia , Infecções por Citomegalovirus/sangue , Inflamação/virologia , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/virologia , Idoso , Proteína C-Reativa/metabolismo , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/patologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Intervalo Livre de Doença , Feminino , Humanos , Inflamação/sangue , Inflamação/patologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Taxa de Sobrevida , Resultado do Tratamento
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