RESUMO
Pediatric solid organ transplant (SOT) recipients face a challenging balance between immunosuppression and graft rejection. While Epstein-Barr Virus (EBV) and cytomegalovirus (HCMV) are known contributors to post-transplant lymphoproliferative disease and graft rejection, respectively, the roles of herpesvirus 6 and 7 (HHV6 and HHV7) and the impact of these herpesviruses on cytokine levels remain unclear, leading to gaps in clinical practice. In this associative study, we measured 17 cytokines using a Bio-Plex assay in a meticulously curated plasma sample pool (N = 158) from pediatric kidney and liver transplant recipients over a one-year follow-up period. The samples included virus-negative and virus-positive cases, either individually or in combination, along with episodes of graft rejection. We observed that the elevation of IL-4, IL-8, and IL-10 correlated with graft rejection. These cytokines were elevated in samples where HCMV or HHV6 were detected alone or where EBV and HHV7 were co-detected. Interestingly, latent EBV, when detected independently, exhibited an immunomodulatory effect by downregulating cytokine levels. However, in co-detection scenarios with ß-herpesviruses, EBV transitioned to a lytic state, also associating with heightened cytokinemia and graft rejection. These findings highlight the complex interactions between the immune response and herpesviruses in transplant recipients. The study advocates for enhanced monitoring of not only EBV and HCMV but also HHV6 and HHV7, providing valuable insights for improved risk assessment and targeted interventions in pediatric SOT recipients.
Assuntos
Citocinas , Citomegalovirus , Rejeição de Enxerto , Herpesvirus Humano 6 , Herpesvirus Humano 7 , Transplante de Rim , Transplante de Fígado , Humanos , Transplante de Rim/efeitos adversos , Citocinas/sangue , Citocinas/metabolismo , Criança , Herpesvirus Humano 6/imunologia , Masculino , Feminino , Pré-Escolar , Transplante de Fígado/efeitos adversos , Citomegalovirus/imunologia , Rejeição de Enxerto/virologia , Rejeição de Enxerto/imunologia , Herpesvirus Humano 4/imunologia , Adolescente , Lactente , Infecções por Herpesviridae/virologia , Infecções por Herpesviridae/imunologia , Transplantados , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/imunologia , HerpesviridaeRESUMO
Viral coinfection among HIV-positive patients, coupled with the development of AIDS, remains a major public health problem. The synergism between the presence of HIV and other viruses has consequences in relation to changes in the severity of the infection, as well as changes in the natural course of both infections. Several polymorphisms present in genes that encode cytokines have a relevant influence on their transcription and consequently on the production of such immunological molecules. The present study evaluated the influence of SNPs located in the promoter regions of genes encoding the cytokines INF-É£, TNF, IL-6, IL-4, and IL-2, as well as their respective plasma concentrations, in patients infected with HIV and/or EBV in the state of Pará. Additionally, this study described the epidemiological profile and compared CD4+ and CD8+ T lymphocyte counts among the groups studied. The associative analysis between the SNPs and plasma cytokine concentrations in different groups showed statistical relevance for three polymorphisms: rs2069762 (IL2), where the GG genotype demonstrated higher IL-2 levels in HIV mono-infected individuals; rs2243250 (IL4), where the CT genotype showed higher IL-4 levels in the control group; and rs2069705 (IFNG), where the TT genotype showed higher IFN-γ levels in the coinfected group. Regarding SNP associations with CD4+/CD8+ counts, significant findings were observed in HIV mono-infected individuals: the rs2069705 (IFNG) polymorphism was linked to higher CD4+ counts with the CT genotype, and rs1799964 (TNF) was associated with higher CD8+ counts with the CC genotype. Therefore, this study provides evidence that the rs2069705 (IFNG) SNP is associated with elevated IFN-γ levels, which may have pathogenic consequences, as depletion of this cytokine is concerning for people living with HIV due to its antiviral properties.
Assuntos
Coinfecção , Citocinas , Infecções por Vírus Epstein-Barr , Infecções por HIV , HIV-1 , Herpesvirus Humano 4 , Polimorfismo de Nucleotídeo Único , Humanos , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/complicações , Brasil/epidemiologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Masculino , Adulto , Feminino , HIV-1/imunologia , HIV-1/genética , Citocinas/genética , Citocinas/sangue , Pessoa de Meia-Idade , Coinfecção/virologia , Coinfecção/imunologia , Coinfecção/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/genética , Genótipo , Linfócitos T CD8-Positivos/imunologia , Adulto Jovem , Contagem de Linfócito CD4 , ImunogenéticaRESUMO
Hodgkin lymphoma is histologically characterised by the presence of Hodgkin (H) and Reed-Sternberg (RS) cells originating from germinal centre B-cells rearranged in the IgV gene. The formation of multinucleated RS cells is a product of telomere organisation in a process initiated by telomere aggregate accumulation in mononuclear H cells and may be mediated by latent membrane protein 1 (LMP-1) expression. LMP-1 is the main oncoprotein of EBV and supports several tumourigenic processes. LMP-1 may rescue proapoptotic B-cells through downregulation of B-cell receptor (BCR) components, mimicking and inducing multiple distinct B-cell signalling pathways to promote proliferation and survival, such as Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-kappa b (NF-кB), and cellular MYC (c-MYC), and inducing telomere instability mainly through Telomere repeat binding factor 2 (TRF2) downregulation to promote the formation of multinucleated RS cells. This review presents recent discoveries regarding the influence of LMP-1 on the surviving cellular signalling, genomic instability and mecanical formation of HRS cells.
Assuntos
Herpesvirus Humano 4 , Doença de Hodgkin , Proteínas da Matriz Viral , Doença de Hodgkin/virologia , Doença de Hodgkin/patologia , Doença de Hodgkin/metabolismo , Humanos , Proteínas da Matriz Viral/metabolismo , Proteínas da Matriz Viral/genética , Herpesvirus Humano 4/genética , Transdução de Sinais , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Instabilidade Genômica , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patologia , Células de Reed-Sternberg/virologiaRESUMO
Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus etiologically associated with benign and malignant diseases. Since the pathogenic mechanisms of EBV are not fully understood, understanding EBV genetic diversity is an ongoing goal. Therefore, the present work describes the genetic diversity of the lytic gene BZLF1 in a sampling of 70 EBV-positive cases from southeastern Brazil. Additionally, together with the genetic regions previously characterized, the aim of the present study was to determine the impact of viral genetic factors that may influence EBV genetic diversity. Accordingly, the phylogenetic analysis of the BZLF1 indicated two main clades with high support, BZ-A and BZ-B (PP > 0.85). Thus, the BZ-A clade was the most diverse clade associated with the main polymorphisms investigated, including the haplotype Type 1 + V3 (p < 0.001). Furthermore, the multigene phylogenetic analysis (MLA) between BZLF1 and the oncogene LMP1 showed specific clusters, revealing haplotypic segregation that previous single-gene phylogenies from both genes failed to demonstrate. Surprisingly, the LMP1 Raji-related variant clusters were shown to be more diverse, associated with BZ-A/B and the Type 2/1 + V3 haplotypes. Finally, due to the high haplotypic diversity of the Raji-related variants, the number of DNA recombination-inducing motifs (DRIMs) was evaluated within the different clusters defined by the MLA. Similarly, the haplotype BZ-A + Raji was shown to harbor a greater number of DRIMs (p < 0.001). These results call attention to the high haplotype diversity of EBV in southeast Brazil and strengthen the hypothesis of the recombinant potential of South American Raji-related variants via the LMP1 oncogene.
Assuntos
Infecções por Vírus Epstein-Barr , Variação Genética , Herpesvirus Humano 4 , Filogenia , Recombinação Genética , Herpesvirus Humano 4/genética , Humanos , Brasil , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/genética , Transativadores/genética , Masculino , Feminino , Haplótipos/genética , Adulto , Proteínas da Matriz Viral/genética , Criança , Pessoa de Meia-Idade , Adolescente , Latência Viral/genética , Pré-Escolar , Adulto JovemRESUMO
OBJECTIVE: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. METHOD: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. RESULTS: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. CONCLUSION: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.
Assuntos
DNA Viral , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica , Recidiva , Humanos , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/virologia , Estudos Retrospectivos , Masculino , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Feminino , DNA Viral/sangue , Pré-Escolar , Criança , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Lactente , Adolescente , Resultado do Tratamento , Relevância ClínicaRESUMO
Epstein-Barr virus (EBV) is an gamma of herpes virus affecting exclusively humans, was the first oncogenic virus described and is associated with over seven different cancers. Curiously, the exchange of genes during viral infections has enabled the evolution of other cellular organisms, favoring new functions and the survival of the host. EBV has been co-evolving with mammals for hundreds of millions of years, and more than 95% of adults have been infected in one moment of their life. The infection is acquired primarily during childhood, in most cases as an asymptomatic infection. However, during adolescence or young adulthood, around 10 to 30% develop infectious mononucleosis. The NK and CD8+ T cells are the cytotoxic cells of the immune system that focus on antiviral responses. Importantly, an essential role of NK and CD8+ T cells has been demonstrated during the control and elimination of EBV-infected cells. Nonetheless, when the cytotoxic function of these cells is compromised, the infection increases the risk of developing lymphoproliferative diseases and cancer, often fatal. In this review, we delineate EBV infection and the importance of cytotoxic responses by NK and CD8+ T cells during the control and elimination of EBV-infected cells. Furthermore, we briefly discuss the main inborn errors of immunity that compromise cytotoxic responses by NK and CD8+ T cells, and how this scenario affects the antiviral response during EBV infection. Finally, we conclude the review by underlying the need for an effective EBV vaccine capable of preventing infection and the consequent development of malignancies and autoimmune diseases.
El virus Epstein-Barr es una variante del herpes virus que afecta exclusivamente a humanos; fue el primer virus oncogénico descrito y se ha relacionado con más de siete diferentes tipos de cáncer. Curiosamente, el intercambio de genes debido a infecciones virales ha permitido la evolución de los organismos celulares, favoreciendo el desarrollo de nuevas funciones y supervivencia del hospedero. El virus Epstein-Barr comparte cientos de millones de años de coevolución con la especie humana y más del 95% de la población adulta mundial se ha infectado en algún momento de su vida. La infección se adquiere principalmente durante la infancia, y en la mayoría de los casos aparece sin ninguna manifestación grave aparente. Sin embargo, en los adolescentes y la población joven-adulta, alrededor de un 10 a 30% evolucionan a mononucleosis infecciosa. Las células NK y T CD8+ son células citotóxicas cruciales durante las respuestas antivirales y se ha demostrado que que controlan y eliminan la infección por el virus Epstein-Barr. No obstante, cuando se afecta su función efectora, el desenlace puede ser fatal. El objetivo de esta revisión es describir la infección por el virus Epstein-Barr y el papel decisivo de las células NK y T CD8+ durante el control y eliminación de la infección. Además, se discuten brevemente los principales defectos genéticos que afectan a estas células y conllevan a la incapacidad para eliminar el virus. Finalmente, se resalta la necesidad de elaborar una vacuna efectiva contra el virus Epstein-Barr y cómo podrían evitarse los procesos neoplásicos y enfermedades autoinmunes.
Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Células Matadoras Naturais , Humanos , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T CD8-Positivos/imunologiaRESUMO
BACKGROUND: This study evaluated the presence of Epstein-Barr virus type 1 (EBV-1) DNA in patients living with HIV, before and after three different topical therapy protocols for oral hairy leukoplakia (OHL). METHODS: The sample consisted of five patients treated with topical solution of 25% podophyllin resin; six with 25% podophyllin resin plus 5% acyclovir cream; and four with 25% podophyllin resin plus 1% penciclovir cream. DNA was extracted from OHL scrapings and amplified by the PCR using specific primers for EBV-1 (EBNA-1). RESULTS: Clinical healing of OHL lesions was observed across all treatment groups over time. At baseline, EBNA-1 was detected in all OHL lesions. After treatment, OHL samples from three patients treated with 25% podophyllin resin plus 5% acyclovir cream and from one patient treated with 25% podophyllin resin plus 1% penciclovir cream exhibited negative EBNA-1 viral gene encoding. Despite the clinical resolution of OHL, 11 patients (73.3%) showed EBNA-1 positivity immediately after the lesion disappeared. Three patients (20%) treated with podophyllin resin displayed both EBNA-1 positivity and a recurrence of OHL, in contrast to no recurrence in the other two groups. CONCLUSIONS: These findings suggest potential associations between treatment formulations, EBNA-1 persistence, and the recurrence of OHL lesions.
Assuntos
Aciclovir , Administração Tópica , Antivirais , DNA Viral , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Leucoplasia Pilosa , Humanos , Feminino , Masculino , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Leucoplasia Pilosa/tratamento farmacológico , Leucoplasia Pilosa/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Aciclovir/uso terapêutico , Aciclovir/administração & dosagem , Pessoa de Meia-Idade , DNA Viral/análise , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/virologia , Adulto , Podofilina/uso terapêutico , Podofilina/administração & dosagem , Resultado do Tratamento , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Reação em Cadeia da Polimerase , Guanina/análogos & derivados , Guanina/uso terapêutico , Guanina/administração & dosagemRESUMO
The Epstein-Barr virus (EBV) is a ubiquitous human pathogen linked to various diseases, including infectious mononucleosis and multiple types of cancer. To control and eliminate EBV, the host's immune system deploys its most potent defenses, including pattern recognition receptors, Natural Killer cells, CD8+ and CD4+ T cells, among others. The interaction between EBV and the human immune system is complex and multifaceted. EBV employs a variety of strategies to evade detection and elimination by both the innate and adaptive immune systems. This demonstrates EBV's mastery of navigating the complexities of the immunological landscape. Further investigation into these complex mechanisms is imperative to advance the development of enhanced therapeutic approaches with heightened efficacy. This review provides a comprehensive overview of various mechanisms known to date, employed by the EBV to elude the immune response, while establishing enduring latent infections or instigate its lytic replication.
Assuntos
Infecções por Vírus Epstein-Barr , Mononucleose Infecciosa , Humanos , Herpesvirus Humano 4 , Linfócitos T , Receptores de Reconhecimento de PadrãoRESUMO
CD4 T cells play a key role in Epstein Barr virus (EBV) infection, by modulating latent antigen expression, and exhibiting cytotoxic and regulatory properties. Our aim was to evaluate the presence of Granzyme B (GZMB) and Foxp3 CD4 T cells at different EBV infection status and latency profiles. We examined CD4, GZMB, Foxp3, IL10, TGF-ß, CD4-GZMB and CD4-Foxp3 expression at the tonsils of pediatric patients with different infective status and EBV latency profiles. CD4+, GZMB+, Foxp3+, CD4-GZMB+ and CD4-Foxp3+ cell counts were higher at the interfollicular region. Higher expression of CD4-GZMB was found in primary infected patients compared to healthy carriers. In patients that expressed latency III antigens, we demonstrated lower CD4+, CD4-GZMB+, CD4-Foxp3+ expression; a negative correlation between the immunoregulatory cytokine IL-10+ and GZMB+ as well as a positive correlation of IL-10+ and CD4+. In patients expressing the lytic protein BMRF1, a positive correlation of TGF-ß+ with CD4-GZMB+ and CD4-Foxp3+ was observed. Our findings indicate that CD4-GZMB+ cells are involved in the restriction of primary EBV infection in pediatric patients, which could partially explain the lack of symptoms, whereas both CD4-GZMB+ and CD4-Foxp3+ cells could be involved in the modulation of latency.
Assuntos
Infecções por Vírus Epstein-Barr , Humanos , Criança , Herpesvirus Humano 4 , Linfócitos T CD4-Positivos , Interleucina-10 , Tonsila Palatina , Fator de Crescimento Transformador beta , Fatores de Transcrição ForkheadRESUMO
EBV+ diffuse large B cell lymphoma (DLBCL) not otherwise specified (NOS) is a new entity confirmed by the World Health Organization (WHO) in 2017. In this new entity, the virus may contribute to a tolerogenic microenvironment. Traces of the virus have been described in DLBCL with more sensitive methods, in cases that were originally diagnosed as negative. The aim of this study was to analyze the expression of immune response genes in the tumor microenvironment to disclose the role of the virus and its traces in DLBCL. In 48 DLBCL cases, the expression of immune response genes and the presence of molecules that induce tolerance, such as TIM3, LAG3 and PDL1 by immunohistochemistry (IHC), were studied. To broaden the study of the microenvironment, tumor-associated macrophages (TMAs) were also explored. No significant differences were observed in the expression of immune response genes in the EBV+ DLBCL and those cases that were EBV- DLBCL but that exhibited viral traces, assessed by ViewRNA assay. Only the EBV+ DLBCL cases displayed a significantly higher increase in the expression of CD8 and cytotoxic T cells detected by gene expression analysis, and of PDL1 in tumor cells and in the expression of CD68 in the tumor microenvironment detected by IHC, not observed in those cases with viral traces. The increase in CD8 and cytotoxic T cells, PDL1 and CD68 markers only in EBV+ DLBCL may indicate that traces of viral infection might not have influence in immune response markers.