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1.
J Clin Pathol ; 73(1): 30-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31315894

RESUMO

AIMS: The purpose of the present study was to elucidate the presence of human herpesvirus 6A (HHV-6A), HHV-6B and HHV-7 in samples of the uterine cervix through detection of viral DNA. We analysed normal tissues, samples with low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). We correlated the presence of HHV-6 and HHV-7 with the finding of human papillomavirus (HPV) in mucosal samples. METHODS: Cervical samples were examined and grouped as follows: group 1 (n=29), normal cytology; group 2 (n=61), samples with LSIL; group 3 (n=35), samples with HSIL. Molecular biology examinations were performed in all samples to detect HHV-6, HHV-7 and HPV DNA and to typify HHV-6 species. RESULTS: Group 1: normal cytology and HPV (-): HHV-6: 6.8% (2/29), HHV-7: 79.3% (23/29); group 2: LSIL and HPV (-): HHV-6: 93.1% (27/29), HHV-7: 96.5% (28/29); LSIL and HPV (+): HHV-6: 0% (0/32), HHV-7: 90.6% (29/32); group 3: HSIL and HPV (-): HHV-6: 20% (2/10), HHV-7: 70% (7/10); HSIL HPV (+): HHV-6: 12% (3/25), HHV-7: 68% (17/25). HHV-6A DNA was not detected in any samples. CONCLUSIONS: (1) Both HHV-6 and HHV-7 infect the mucosal cells of the cervix with higher prevalence of HHV-7. (2) The higher prevalence of HHV-6 in LSIL HPV (-) samples compared with those with normal cytology indicates that it constitutes a possible risk factor for atypia production. (3) The presence of HHV-7 in all samples questions its role in the production of atypia. (4) The finding of HHV-6 and HHV-7 suggests that the cervical mucosa is a possible transmission pathway for these viruses.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , DNA Viral/genética , Herpesvirus Humano 6/genética , Herpesvirus Humano 7/genética , Técnicas de Diagnóstico Molecular , Infecções por Roseolovirus/diagnóstico , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adolescente , Adulto , Argentina , Neoplasia Intraepitelial Cervical/genética , Neoplasia Intraepitelial Cervical/virologia , Feminino , Testes de DNA para Papilomavírus Humano , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Infecções por Roseolovirus/genética , Infecções por Roseolovirus/transmissão , Infecções por Roseolovirus/virologia , Lesões Intraepiteliais Escamosas Cervicais/genética , Lesões Intraepiteliais Escamosas Cervicais/virologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Adulto Jovem
2.
Epilepsy Res ; 153: 34-39, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30953871

RESUMO

Infection with Human Herpesvirus-6 (HHV-6) has been associated with different epilepsy syndromes, including febrile seizures and status epilepticus, acute symptomatic seizures secondary to encephalitis and temporal lobe epilepsy. This neurotropic DNA virus is ubiquitous and primary infection occurs in up to 80% of children by age two years. While two viral variants have been identified, HHV-6B is the one that has been primarily linked to disease in humans, including epilepsy. After initial viremia, the virus can establish chronic latency in brain tissue, peripherally in tonsils and salivary glands and infect several different cell lines by binding to the complement regulator CD-46. In this review we will focus on discussing the evidence linking HHV-6 infection to different epilepsy syndromes and analyzing proposed pathogenic mechanisms.


Assuntos
Epilepsia/complicações , Epilepsia/virologia , Herpesvirus Humano 6/patogenicidade , Infecções por Roseolovirus/complicações , Herpesvirus Humano 6/genética , Humanos , Infecções por Roseolovirus/virologia
3.
Transpl Infect Dis ; 21(1): e13003, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30256500

RESUMO

BACKGROUND: Human herpesvirus 6 (HHV6) is a cause of post-transplant acute limbic encephalitis (PALE). Seizures are associated with this disorder yet no predictive biomarkers have been identified. The objective of this study was to evaluate lab and neurodiagnostic biomarkers in patients with HHV6 associated PALE. METHODS: A retrospective chart review was performed at our institutions between 2000 and 2017. Patients were identified through a clinical database. Inclusion criteria included: age less than 18 years, HHV6 (quantitative real-time PCR or meningoencephalitis panel) tested in CSF and serum. Biomarkers of serum and CSF viral load, EEG, and MRI were reviewed along with clinical data. RESULTS: In total, 11 patients met inclusion criteria. All patients had undergone hematopoietic stem cell transplantation. Five of 11 patients had seizures as part of their clinical course, all being controlled with antiepileptic monotherapy. Seizure semiology was focal-onset in three cases and generalized in two. Neuroimaging was normal in all patients within seven days but six patients developed T2 signal intensities in the temporal lobes on repeat imaging between 14-28 days. The median CSF HHV6 viral load for all patients was 47 300 copies/mL although the median viral load was 2586 copies/mL in patients who had seizure compared to 473 969 copies/mL in those who had not (P = 0.02). Those with seizures tended to be younger (median 6.5 years compared to 11 years, P = 0.27). All patients with seizures had an EEG with 80% demonstrating abnormalities. CONCLUSION: In patients with post-hematopoietic stem cell transplant HHV6 associated PALE, lower CSF viral load may be associated with a higher likelihood to have seizures. This may indicate a primary infection as opposed to secondary reactivation phenomenon.


Assuntos
Encefalite Viral/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6/isolamento & purificação , Encefalite Límbica/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Infecções por Roseolovirus/diagnóstico , Convulsões/diagnóstico , Doença Aguda , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Criança , Eletroencefalografia , Encefalite Viral/complicações , Encefalite Viral/virologia , Feminino , Humanos , Encefalite Límbica/sangue , Encefalite Límbica/líquido cefalorraquidiano , Encefalite Límbica/virologia , Imagem por Ressonância Magnética , Masculino , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/líquido cefalorraquidiano , Complicações Pós-Operatórias/virologia , Estudos Retrospectivos , Infecções por Roseolovirus/complicações , Infecções por Roseolovirus/virologia , Convulsões/sangue , Convulsões/líquido cefalorraquidiano , Convulsões/virologia , Carga Viral
4.
J Virol ; 93(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429336

RESUMO

Human herpesvirus 6B (HHV-6B) DNA is frequently detected in human samples. Diagnostic assays distinguishing HHV-6B reactivation from latency are limited. This has impaired strategies to diagnose and treat HHV-6B-associated diseases. We used RNA sequencing to characterize and compare the HHV-6B transcriptome in multiple sample types, including (i) whole blood from hematopoietic cell transplant (HCT) recipients with and without HHV-6B plasma viremia, (ii) tumor tissue samples from subjects with large B cell lymphoma infected with HHV-6B, (iii) lymphoblastoid cell lines (LCLs) from subjects with inherited chromosomally integrated HHV-6B or latent infection with HHV-6B, and (iv) HHV-6B Z29 infected SupT1 CD4+ T cells. We demonstrated substantial overlap in the HHV-6B transcriptome observed in in vivo and in vitro samples, although there was variability in the breadth and quantity of gene expression across samples. The HHV-6B viral polymerase gene U38 was the only HHV-6B transcript detected in all next-generation RNA sequencing (RNA-seq) data sets and was one of the most highly expressed genes. We developed a novel reverse transcription-PCR assay targeting HHV-6B U38, which identified U38 mRNA in all tested whole-blood samples from patients with concurrent HHV-6B viremia. No HHV-6B U38 transcripts were detected by RNA-seq or reverse transcription-real-time quantitative PCR (RT-qPCR) in whole-blood samples from subjects without HHV-6B plasma detection or from latently infected LCLs. A RT-qPCR assay for HHV-6B U38 may be useful to identify lytic HHV-6B infection in nonplasma samples and samples from individuals with inherited chromosomally integrated HHV-6B. This study also demonstrates the feasibility of transcriptomic analyses for HCT recipients.IMPORTANCE Human herpesvirus 6B (HHV-6B) is a DNA virus that infects most children within the first few years of life. After primary infection, HHV-6B persists as a chronic, latent infection in many cell types. Additionally, HHV-6B can integrate into germ line chromosomes, resulting in individuals with viral DNA in every nucleated cell. Given that PCR to detect viral DNA is the mainstay for diagnosing HHV-6B infection, the characteristics of HHV-6B infection complicate efforts to distinguish between latent and active viral infection, particularly in immunocompromised patients who have frequent HHV-6B reactivation. In this study, we used RNA sequencing to characterize the HHV-6B gene expression profile in multiple sample types, and our findings identified evidence-based targets for diagnostic tests that distinguish between latent and active viral infection.


Assuntos
Herpesvirus Humano 6/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Infecções por Roseolovirus/diagnóstico , Transcriptoma , Proteínas Virais/genética , Viremia/diagnóstico , Ativação Viral , Latência Viral , Adulto , Idoso , Biomarcadores/análise , Estudos de Casos e Controles , Citocinas/sangue , DNA Viral , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Infecções por Roseolovirus/genética , Infecções por Roseolovirus/virologia , Viremia/genética , Viremia/virologia
5.
Transpl Infect Dis ; 21(1): e13024, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30414316

RESUMO

BACKGROUND: Human herpesvirus 6 (HHV-6) encephalitis is a known life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, few studies have focused on the occurrence of HHV-6 encephalitis in patients receiving mycophenolate mofetil (MMF) combined with a calcineurin inhibitor as prophylaxis for graft-versus-host disease (GVHD). This study aimed to investigate the impact of MMF administered for GVHD prophylaxis in the occurrence of HHV-6 encephalitis after allo-HSCT and the characteristics of this condition. METHODS AND RESULTS: We retrospectively analyzed 73 patients who underwent allo-HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2-3 g/d) was administered along with a calcineurin inhibitor. Seven patients (8.0%) developed encephalitis due to HHV-6. The median period from allo-HSCT to the onset of HHV-6 encephalitis was 23 days (range, 17-98 days). The cumulative incidence of HHV-6 encephalitis on day 100 after treatment was 12% and 6% in patients who underwent cord blood transplantation (CBT) and non-CBT (ie, bone marrow transplantation and peripheral blood stem cell transplantation), respectively (P = 0.344). Neurological symptoms of encephalitis were more severe in non-CBT cases than those in CBT cases. All patients diagnosed with HHV-6 encephalitis were treated with ganciclovir or foscarnet. None of the enrolled patients died from HHV-6 encephalitis. CONCLUSIONS: Mycophenolate mofetil may have the potential to increase the frequency of severe HHV-6 encephalitis in patients undergoing CBT and non-CBT. Thus, MMF should be administered with caution, and patients should be monitored closely for HHV-6 encephalitis even those who did not undergo CBT.


Assuntos
Encefalite Viral/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/efeitos adversos , Ácido Micofenólico/efeitos adversos , Infecções por Roseolovirus/epidemiologia , Adulto , Idoso , Antivirais/uso terapêutico , Inibidores de Calcineurina/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Encefalite Viral/diagnóstico , Encefalite Viral/tratamento farmacológico , Encefalite Viral/virologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/cirurgia , Herpesvirus Humano 6/isolamento & purificação , Humanos , Imunossupressão/efeitos adversos , Imunossupressão/métodos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Infecções por Roseolovirus/diagnóstico , Infecções por Roseolovirus/tratamento farmacológico , Infecções por Roseolovirus/virologia , Índice de Gravidade de Doença , Transplante Homólogo/efeitos adversos , Adulto Jovem
6.
Artigo em Inglês | MEDLINE | ID: mdl-30398125

RESUMO

BACKGROUND AND OBJECTIVE: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis that can be limited to the skin but may also affect other organs. Often, its cause is unknown. LCV has previously been reported to occur with the reactivation of human herpesvirus 6 (HHV-6). Here, we report a second instance of HHV-6 reactivation in a 43-year-old woman with idiopathic cutaneous LCV. CASE DESCRIPTION: In this case, the patient was immunocompetent, and testing revealed that she had inherited chromosomally integrated human herpesvirus 6 variant A (iciHHV6-A) with a parallel skin infection of HHV-6B. The integrated ciHHV-6A strain was found to be transcriptionally active in the blood, while HHV-6B late antigen was detected in a skin biopsy. The patient's rash was not accompanied by fever nor systemic symptoms and resolved over four weeks without any therapeutic intervention. CONCLUSION: In light of the transcriptional activity documented in our case, further examination of a possible role for HHV-6 in the etiology of LCV is warranted.


Assuntos
Exantema Súbito/complicações , Herpesvirus Humano 6 , Imunocompetência , Vasculite Leucocitoclástica Cutânea/complicações , Adulto , Coinfecção/complicações , Coinfecção/diagnóstico , Coinfecção/imunologia , Coinfecção/virologia , Exantema Súbito/diagnóstico , Exantema Súbito/imunologia , Exantema Súbito/virologia , Feminino , Herpesvirus Humano 6/classificação , Herpesvirus Humano 6/isolamento & purificação , Humanos , Infecções por Roseolovirus/complicações , Infecções por Roseolovirus/imunologia , Infecções por Roseolovirus/virologia , Vasculite Leucocitoclástica Cutânea/diagnóstico , Vasculite Leucocitoclástica Cutânea/imunologia , Vasculite Leucocitoclástica Cutânea/virologia
7.
Transpl Infect Dis ; 21(1): e13014, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30346638

RESUMO

BACKGROUND: In recent years, liver transplantation (LT) has become a well-accepted therapeutic modality for children with end-stage liver disease, with transplantation surgery being performed at a younger age. Human herpes virus 6 (HHV-6) infection occurs in most children within the first 2 years of life, therefore, data on primary HHV-6 infection in pediatric liver transplant recipients is scarce. OBJECTIVE: To describe the course of primary HHV-6 infection after pediatric LT. METHODS: Medical files, between the years 2015-2016, of post-LT pediatric patients with suspected primary HHV-6 infection were reviewed. Clinical and laboratory data for enrolled cases were evaluated. Primary infection was defined as DNAemia in children who were seronegative prior to transplantation or seroconversion from negative to positive IgG posttransplantation. RESULTS: Four cases of primary HHV-6 (type B) infection were identified among the 26 children who had undergone LT at our center during the study period. All patients were <1 year old and presented with fever, hepatitis, and elevated inflammatory markers, most (75%) within a short-period posttransplantation. All were initially treated with empiric antibiotics for a suspected bacterial infection and three underwent liver biopsy, one showing signs of rejection. Three were treated with antiviral therapy with a gradual resolution of symptoms. DISCUSSION: Primary HHV-6 should be taken into account in young children shortly after LT, especially when presenting with fever and elevated liver enzymes. Treatment with antiviral therapy should be considered. CONCLUSIONS: In young infants post-LT, a high index of suspicion may promote early detection of HHV-6 primary infection and prevent serious complications.


Assuntos
Febre/diagnóstico , Herpesvirus Humano 6/isolamento & purificação , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Infecções por Roseolovirus/diagnóstico , Adolescente , Anticorpos Antivirais/sangue , Anticorpos Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Biomarcadores/análise , Biópsia , Criança , Pré-Escolar , DNA Viral/sangue , DNA Viral/isolamento & purificação , Feminino , Febre/sangue , Febre/virologia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/patologia , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/imunologia , Humanos , Lactente , Fígado/patologia , Fígado/virologia , Masculino , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/virologia , Estudos Retrospectivos , Infecções por Roseolovirus/sangue , Infecções por Roseolovirus/tratamento farmacológico , Infecções por Roseolovirus/virologia
8.
Viruses ; 10(12)2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30572622

RESUMO

Herpesviruses are common components of the human microbiome that become clinically relevant when a competent immunosurveillance is compromised, such as in transplantation. Members of the beta and gamma subfamilies are associated with a wide diversity of pathologies, including end-organ disease and cancer. In this study, we developed a multiplex qPCR technique with high specificity, sensitivity, efficiency and predictability that allowed the simultaneous detection and quantification of beta and gamma human herpesviruses. The technique was tested in a cohort of 34 kidney- or liver-transplanted pediatric patients followed up for up to 12 months post-transplant. Viral load was determined in 495 leukocyte-plasma paired samples collected bi-weekly or monthly. Human herpesvirus (HHV) 7 was the herpesvirus most frequently found in positive samples (39%), followed by Epstein-Barr virus (EBV) (20%). Also, EBV and HHV7 were present in the majority of coinfection episodes (62%). The share of positive samples exclusively detected either in leukocytes or plasma was 85%, suggesting that these herpesviruses tended to take a latent or lytic path in an exclusive manner. Infection by human cytomegalovirus (HCMV) and HHV6, as well as coinfection by EBV/HHV7 and EBV/HHV6/HHV7, were associated with graft rejection (RR = 40.33 (p = 0.0013), 5.60 (p = 0.03), 5.60 (p = 0.03) and 17.64 (p = 0.0003), respectively). The routine monitoring of beta and gamma herpesviruses should be mandatory in transplant centers to implement preventive strategies.


Assuntos
Coinfecção/diagnóstico , Infecções por Vírus Epstein-Barr/diagnóstico , Rejeição de Enxerto/etiologia , Transplante de Órgãos/efeitos adversos , Infecções por Roseolovirus/diagnóstico , Adolescente , Criança , Coinfecção/virologia , Primers do DNA/genética , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/virologia , Feminino , Rejeição de Enxerto/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 6/genética , Herpesvirus Humano 7/genética , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Estudos Prospectivos , Infecções por Roseolovirus/virologia , Sensibilidade e Especificidade , Carga Viral
9.
Proc Natl Acad Sci U S A ; 115(44): 11292-11297, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30322946

RESUMO

Pathogens, particularly human herpesviruses (HHVs), are implicated as triggers of disease onset/progression in multiple sclerosis (MS) and other neuroinflammatory disorders. However, the time between viral acquisition in childhood and disease onset in adulthood complicates the study of this association. Using nonhuman primates, we demonstrate that intranasal inoculations with HHV-6A and HHV-6B accelerate an MS-like neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE). Although animals inoculated intranasally with HHV-6 (virus/EAE marmosets) were asymptomatic, they exhibited significantly accelerated clinical EAE compared with control animals. Expansion of a proinflammatory CD8 subset correlated with post-EAE survival in virus/EAE marmosets, suggesting that a peripheral (viral?) antigen-driven expansion may have occurred post-EAE induction. HHV-6 viral antigen in virus/EAE marmosets was markedly elevated and concentrated in brain lesions, similar to previously reported localizations of HHV-6 in MS brain lesions. Collectively, we demonstrate that asymptomatic intranasal viral acquisition accelerates subsequent neuroinflammation in a nonhuman primate model of MS.


Assuntos
Herpesvirus Humano 6/patogenicidade , Inflamação/virologia , Esclerose Múltipla/virologia , Primatas/virologia , Animais , Encéfalo/virologia , Callithrix , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/virologia , Feminino , Masculino , Infecções por Roseolovirus/virologia
10.
J Investig Clin Dent ; 9(4): e12356, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30062730

RESUMO

AIM: The aim of the present study was to describe the salivary shedding of human herpesviruses (HHV) in renal transplant recipients and to observe the oral manifestations in this group. METHODS: A prospective case-control study was conducted with a study group of 20 renal transplant recipients and a control group of 20 non-transplanted, immunocompetent individuals. Clinical examination evaluated the presence of drug-induced gingival overgrowth (DIGO), salivary flow, and caries. Stimulated saliva was collected from both groups, with HHV being detected by using real-time polymerase chain reaction. RESULTS: The mean age of the study group was 45.90 ± 9.89 years, with 55% (11/20) being female, 60% (12/20) being Caucasian, 65% (13/20) having a deceased donor, and 70% (14/20) having used tacrolimus as the main immunosuppressive drug. Renal transplant recipients had shedding of more herpesviruses compared to the control group, with the exception of HHV-7. Statistical significance was found for herpes simplex virus-1 (HSV-1) (P = 0.017) and cytomegalovirus (P = 0.035). DIGO was observed in seven patients (35%), with 35% (7/20) presenting with decreased salivary flow and four (20%) reporting xerostomia. CONCLUSION: Renal transplant recipients excreted herpesviruses more often than control individuals, especially HSV-1. Decreased salivary flow and xerostomia were more frequent in patients who used tacrolimus, whereas those who used cyclosporine had more cases of DIGO.


Assuntos
Infecções por Herpesviridae/epidemiologia , Herpesviridae , Transplante de Rim/efeitos adversos , Saliva/virologia , Brasil/epidemiologia , Estudos de Casos e Controles , Ciclosporina/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpes Simples/epidemiologia , Herpes Simples/virologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 1 , Herpesvirus Humano 4 , Herpesvirus Humano 6 , Herpesvirus Humano 7 , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/virologia , Tacrolimo/uso terapêutico , Eliminação de Partículas Virais/efeitos dos fármacos
11.
Int J Hematol ; 108(6): 580-587, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30155589

RESUMO

Cancer-related fatigue (CRF) is one of the adverse events in multiple myeloma (MM) patients treated with cytotoxic agents, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs) such as bortezomib, lenalidomide, and thalidomide. The aims of our study were to prospectively analyze the clinical significance of CRF, and to evaluate the cumulative incidence of CRF and the survival rates of 16 MM patients who were treated with PIs and IMiDs. Reactivation of salivary human herpes virus (HHV)-6 and HHV-7 was analyzed using real-time quantitative polymerase chain reaction (qPCR). CRF was evaluated using a visual analog scale (VAS). Eleven newly diagnosed multiple myeloma (NDMM) and five relapsed or refractory MM patients were enrolled in this study. The cumulative incidence of CRF was 54.9%. The treatment types were not associated with the CRF incidence. The cumulative incidence of reactivation of HHV-6 and HHV-7 was 73.1% and 45.6%, respectively. However, the reactivation of HHV-6 and HHV-7 was not related to CRF. The overall survival (OS) and progression-free survival (PFS) in NDMM patients with CRF was significantly shorter than in those without CRF. In conclusion, CRF was one of the major symptoms in MM patients, and predicted shorter OS and PFS in NDMM patients.


Assuntos
Fadiga/diagnóstico , Fadiga/etiologia , Mieloma Múltiplo/complicações , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Fadiga/epidemiologia , Fadiga/terapia , Feminino , Herpesvirus Humano 6/genética , Herpesvirus Humano 7/genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Infecções por Roseolovirus/complicações , Infecções por Roseolovirus/virologia
12.
Neuron ; 99(1): 56-63.e3, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-30001512

RESUMO

Amyloid-ß peptide (Aß) fibrilization and deposition as ß-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aß is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aß antimicrobial activities. Thus, infection can seed and dramatically accelerate ß-amyloid deposition. Here, we show Aß oligomers bind herpesvirus surface glycoproteins, accelerating ß-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce ß-amyloidosis in brain. These data support the notion that Aß might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aß amyloidosis.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Encéfalo/metabolismo , Encefalite Viral/metabolismo , Herpesviridae , Doença de Alzheimer/virologia , Amiloidose/virologia , Animais , Encéfalo/virologia , Células Cultivadas , Modelos Animais de Doenças , Encefalite por Herpes Simples/metabolismo , Encefalite por Herpes Simples/virologia , Encefalite Viral/virologia , Herpesvirus Humano 1 , Herpesvirus Humano 6 , Humanos , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Neurônios , Placa Amiloide/metabolismo , Infecções por Roseolovirus/metabolismo , Infecções por Roseolovirus/virologia
13.
Neuron ; 99(1): 64-82.e7, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29937276

RESUMO

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.


Assuntos
Doença de Alzheimer/virologia , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/virologia , Encefalite Viral/virologia , Herpesvirus Humano 6 , Herpesvirus Humano 7 , Infecções por Roseolovirus/virologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/genética , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Clusterina/genética , Estudos de Coortes , Encefalite Viral/genética , Encefalite Viral/metabolismo , Encefalite Viral/patologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Genômica , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , Microbiota , Proteínas Monoméricas de Montagem de Clatrina/genética , Proteínas Nucleares/genética , Presenilina-1/genética , Proteômica , Infecções por Roseolovirus/genética , Infecções por Roseolovirus/metabolismo , Infecções por Roseolovirus/patologia , Proteínas Supressoras de Tumor/genética , Carga Viral
14.
J Med Virol ; 90(10): 1636-1642, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29905966

RESUMO

The objectives of the work are to elucidate the incidence and virological findings of chromosomally integrated human herpesvirus 6 (ciHHV-6) in Japanese population and to analyze an association between ciHHV-6 and the clinical manifestation of exanthema subitum (ES). Real-time polymerase chain reaction was performed to determine HHV-6 DNA loads in 2347 cord blood samples from healthy neonates (cohort A), febrile children less than 5 years old (cohort B), and hematopoietic cell transplant recipients (cohort C). CiHHV-6 was confirmed by detection of high copy numbers of viral DNA in somatic cells. The integration site was determined by fluorescent in situ hybridization analysis. In the ciHHV-6 subjects of cohorts A and B, HHV-6 antibody titers were measured, the history of ES was obtained, and the incidence of ES was compared with non-ciHHV-6 children without primary HHV-6B infection in the cohort B. CiHHV-6 was detected in 14 (0.60%) of the 2347 samples: A (6/1006, 0.60%), B (6/790, 0.76%), and C (2/551, 0.36%). The integration sites were on chromosome 22q in seven cases, Yp in two cases, and 17q and Xp in one case. No past history of ES was observed in 11 of the 12 subjects. Nine children with ciHHV-6 underwent serological analysis and were found to be positive for HHV-6 IgG antibodies. Incidence of ES was statistically higher in the control subjects than the ciHHV-6 subjects (P = 0.0039). In Japan, the frequency of ciHHV-6 was 0.60%. A high incidence of ciHHV-6A, specifically in chromosome 22, is a characteristic finding among the Japanese. CiHHV-6 may interfere with the clinical symptoms of primary HHV-6B infection.


Assuntos
Herpesvirus Humano 6/genética , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/virologia , Anticorpos Antivirais/sangue , Grupo com Ancestrais do Continente Asiático , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hibridização in Situ Fluorescente , Incidência , Lactente , Recém-Nascido , Japão , Masculino , Reação em Cadeia da Polimerase em Tempo Real
15.
Adv Exp Med Biol ; 1045: 145-165, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896667

RESUMO

Recently, human herpesvirus 6A and 6B (HHV-6A and HHV-6B) were classified into distinct species. Although these two viruses share many similarities, cell tropism is one of their striking differences, which is partially because of the difference in their entry machinery. Many glycoproteins of HHV-6A/B have been identified and analyzed in detail, especially in their functions during entry process into host cells. Some of these glycoproteins were unique to HHV-6A/B. The cellular factors associated with these viral glycoproteins (or glycoprotein complex) were also identified in recent years. Detailed interaction analyses were also conducted, which could partially prove the difference of entry machinery in these two viruses. Although there are still issues that should be addressed, all the knowledges that have been earned in recent years could not only help us to understand these viruses' entry mechanism well but also would contribute to the development of the therapy and/or prophylaxis methods for HHV-6A/B-associated diseases.


Assuntos
Glicoproteínas/metabolismo , Herpesvirus Humano 6/metabolismo , Infecções por Roseolovirus/virologia , Proteínas do Envelope Viral/metabolismo , Animais , Glicoproteínas/genética , Herpesvirus Humano 6/genética , Humanos , Proteínas do Envelope Viral/genética
16.
Adv Exp Med Biol ; 1045: 209-226, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896669

RESUMO

Upon infection and depending on the infected cell type, human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) can replicate or enter a state of latency. HHV-6A and HHV-6B can integrate their genomes into host chromosomes as one way to establish latency. Viral integration takes place near the subtelomeric/telomeric junction of chromosomes. When HHV-6 infection and integration occur in gametes, the virus can be genetically transmitted. Inherited chromosomally integrated HHV-6 (iciHHV-6)-positive individuals carry one integrated HHV-6 copy per somatic cell. The prevalence of iciHHV-6+ individuals varies between 0.6% and 2%, depending on the geographical region sampled. In this chapter, the mechanisms leading to viral integration and reactivation from latency, as well as some of the biological and medical consequences associated with iciHHV-6, were discussed.


Assuntos
Cromossomos Humanos/virologia , Herpesvirus Humano 6/fisiologia , Infecções por Roseolovirus/virologia , Integração Viral , Animais , DNA Viral/genética , DNA Viral/metabolismo , Herpesvirus Humano 6/genética , Humanos , Telômero/virologia
17.
Methods Mol Biol ; 1768: 99-109, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29717439

RESUMO

Droplet digital™ polymerase chain reaction (ddPCR™) is a unique digital PCR technique that allows for absolute quantification of nucleic acid samples. This technique operates on the basis of amplification within water-oil emulsion droplets and can detect very small quantities of target molecules, yielding extremely precise data. Here, we describe in detail a ddPCR procedure for multiplexed detection of two clinically relevant herpesviruses, HHV-6A and HHV-6B.


Assuntos
Coinfecção/diagnóstico , DNA Viral/isolamento & purificação , Herpesvirus Humano 6/isolamento & purificação , Reação em Cadeia da Polimerase Multiplex/métodos , Infecções por Roseolovirus/diagnóstico , Coinfecção/virologia , Herpesvirus Humano 6/genética , Humanos , Reação em Cadeia da Polimerase Multiplex/instrumentação , Infecções por Roseolovirus/virologia
18.
J Med Virol ; 90(9): 1532-1540, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29727474

RESUMO

Skin disorders vary greatly in symptom and severity, and the causes of these disorders are largely unknown. Human herpesvirus (HHV) has been shown to cause many diseases. However, the prevalence and correlation of each HHV infection with different skin disorders remains obscure. To reveal the potential link of a certain type of skin disease with herpesvirus infection, a total of 272 patient tissues with inflammatory or neoplastic skin diseases including 7 subtypes in Shanghai, China, were investigated. We found that the overall prevalence of HHV-6A in inflammatory or neoplastic skin tissues is the most common (40.3%), followed by Epstein-Barr virus (17.6%), Kaposi's sarcoma-associated herpesvirus (KSHV; 9.2%), HHV-6B (4.4%), human cytomegalovirus (1.1%), and varicella-zoster virus (0.7%); albeit the co-infection of HHV-6A, Epstein-Barr virus, and KSHV presents to a less extent and none of HSV-1, HSV-2, or HHV-7 were detected. Moreover, HHV-6A infection is highly associated with nevocytic nevus and seborrheic dermatitis/keratosis diseases, which mainly occur in the head and the neck or the lower limb. Despite no significant difference among the HHV infections in different age groups of skin patient tissues, the distribution of KSHV infection was exclusively and significantly higher (~3.7-fold) in male skin patients.


Assuntos
Dermatite Seborreica/virologia , Herpesvirus Humano 6/isolamento & purificação , Nevo/virologia , Infecções por Roseolovirus/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prevalência , Infecções por Roseolovirus/virologia , Pele/virologia , Adulto Jovem
19.
Transpl Infect Dis ; 20(4): e12916, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29797616

RESUMO

BACKGROUND: We sought to determine whether late-phase human herpesvirus 6B (HHV-6B) infection in hematopoietic stem cell transplant (HSCT) recipients was associated with serious outcomes and mortality. METHODS: The occurrence and course of HHV-6B infection was monitored for at least 60 days after transplant using virus isolation and real-time polymerase chain reaction. Risk factors for late-phase HHV-6B infection were examined, and the propensity score was calculated with significant risk factors. The inverse probability-weighted multivariable logistic regression analysis was performed to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI) for mortality. RESULTS: Late-phase HHV-6B infection was observed in 12/89 (13.5%) of the HSCT recipients. Older age (OR: 10.3, 95% CI: 2.1/72.9, P = .0027), hematologic malignancy (OR: 10.3, 95% CI: 1.8/97.1, P = .0063), unrelated donor transplantation (OR: 5.3, 95% CI: 1.1/36.0, P = .0345), and sex-mismatched donor transplantation (OR: 6.3, 95% CI: 1.4/39.5, P = .0149) were identified as risk factors for late-phase HHV-6B infection. Fifteen subjects died (17%). Inverse probability-weighted multivariable logistic model analysis revealed that late-phase HHV-6B infection was an independent risk factor for mortality (OR: 4.2, 95% CI: 1.7/11.0, P = .0012). Among 5 of the fatal cases of late-phase HHV-6B infection, viral infection might be associated with severe clinical manifestations. CONCLUSION: Late-phase HHV-6B infection in HSCT recipients was associated with worse outcomes. The full spectrum of clinical features of the infection has not been fully elucidated, and therefore, recipients with high-risk factors for late-phase HHV-6B infection should be carefully monitored.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6/fisiologia , Hospedeiro Imunocomprometido , Infecções por Roseolovirus/epidemiologia , Ativação Viral , Fatores Etários , Criança , DNA Viral/isolamento & purificação , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 6/isolamento & purificação , Humanos , Imunossupressão/efeitos adversos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Roseolovirus/imunologia , Infecções por Roseolovirus/virologia , Fatores Sexuais , Fatores de Tempo
20.
Clin Infect Dis ; 67(7): 1125-1128, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-29635334

RESUMO

A review of 15 patients who tested positive for human herpesvirus 6 (HHV-6) on the FilmArray Meningitis/Encephalitis panel revealed that the majority were unlikely to have HHV-6 encephalitis. Criteria to assist interpretation of HHV-6 positive results are presented.


Assuntos
Herpesvirus Humano 6/isolamento & purificação , Meningite/virologia , Técnicas de Diagnóstico Molecular/métodos , Infecções por Roseolovirus/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalite Viral/virologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Masculino , Meningite/diagnóstico , Pessoa de Meia-Idade , Infecções por Roseolovirus/diagnóstico
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