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1.
J Med Case Rep ; 16(1): 424, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36336687

RESUMO

BACKGROUND: Kaposi sarcoma is a vascular tumor highly related to human herpesvirus-8 and Kaposi sarcoma-associated herpesvirus. Kaposi sarcoma usually manifests as skin or mucosal lesions; involvement in visceral organs such as the gastrointestinal tract is rare. Kaposi sarcoma can occur in immunocompromised patients receiving immunosuppressive therapy, in which case it is known as iatrogenic Kaposi sarcoma or drug-induced Kaposi sarcoma. Intestinal Kaposi sarcoma in patients with inflammatory bowel disease is extremely rare. CASE PRESENTATION: A 46-year-old East Asian male with recently diagnosed Crohn's disease was administered azathioprine and prednisolone; however, the patient complained of persistent abdominal pain and diarrhea following treatment. Endoscopy revealed small bowel Kaposi sarcoma. The patient was treated with systemic chemotherapy successfully without relapse. CONCLUSIONS: This is the fifth case of Kaposi sarcoma developed over the small intestine in a patient with Crohn's disease following administration of immunomodulators. Additionally, this case indicated that even short-term immunomodulator use can induce Kaposi sarcoma in patients with inflammatory bowel disease. Thus, in patients with inflammatory bowel disease, if symptoms are aggravated or do not abate after immunomodulators prescription, and before intending to upgrade immunomodulators, endoscopy should be considered. Finally, chemotherapy can also be considered if both medication withdrawal and surgical intervention are not feasible.


Assuntos
Doença de Crohn , Herpesvirus Humano 8 , Doenças Inflamatórias Intestinais , Sarcoma de Kaposi , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Sarcoma de Kaposi/induzido quimicamente , Sarcoma de Kaposi/tratamento farmacológico , Recidiva Local de Neoplasia , Fatores Imunológicos/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Intestino Delgado/diagnóstico por imagem , Doença Iatrogênica
2.
J Virol ; 96(22): e0146922, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36326276

RESUMO

Herpesviral infection reflects thousands of years of coevolution and the constant struggle between virus and host for control of cellular gene expression. During Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication, the virus rapidly seizes control of host gene expression machinery by triggering a massive RNA decay event via a virally encoded endoribonuclease, SOX. This virus takeover strategy decimates close to 80% of cellular transcripts, reallocating host resources toward viral replication. The host cell, however, is not entirely passive in this assault on RNA stability. A small pool of host transcripts that actively evade SOX cleavage has been identified over the years. One such "escapee," C19ORF66 (herein referred to as Shiftless [SHFL]), encodes a potent antiviral protein capable of restricting the replication of multiple DNA and RNA viruses and retroviruses, including KSHV. Here, we show that SHFL restricts KSHV replication by targeting the expression of critical viral early genes, including the master transactivator protein, KSHV ORF50, and thus subsequently the entire lytic gene cascade. Consistent with previous reports, we found that the SHFL interactome throughout KSHV infection is dominated by RNA-binding proteins that influence both translation and protein stability, including the viral protein ORF57, a crucial regulator of viral RNA fate. We next show that SHFL affects cytoplasmic RNA granule formation, triggering the disassembly of processing bodies. Taken together, our findings provide insights into the complex relationship between RNA stability, RNA granule formation, and the antiviral response to KSHV infection. IMPORTANCE In the past 5 years, SHFL has emerged as a novel and integral piece of the innate immune response to viral infection. SHFL has been reported to restrict the replication of multiple viruses, including several flaviviruses and the retrovirus HIV-1. However, to date, the mechanism(s) by which SHFL restricts DNA virus infection remains largely unknown. We have previously shown that following its escape from KSHV-induced RNA decay, SHFL acts as a potent antiviral factor, restricting nearly every stage of KSHV lytic replication. In this study, we set out to determine the mechanism by which SHFL restricts KSHV infection. We demonstrate that SHFL impacts all classes of KSHV genes and found that SHFL restricts the expression of several key early genes, including KSHV ORF50 and ORF57. We then mapped the interactome of SHFL during KSHV infection and found several host and viral RNA-binding proteins that all play crucial roles in regulating RNA stability and translation. Lastly, we found that SHFL expression influences RNA granule formation both outside and within the context of KSHV infection, highlighting its broader impact on global gene expression. Collectively, our findings highlight a novel relationship between a critical piece of the antiviral response to KSHV infection and the regulation of RNA-protein dynamics.


Assuntos
Infecções por Herpesviridae , Herpesvirus Humano 8 , Humanos , Herpesvirus Humano 8/fisiologia , Regulação Viral da Expressão Gênica , Grânulos de Ribonucleoproteínas Citoplasmáticas , Replicação Viral , Infecções por Herpesviridae/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Expressão Gênica , Antivirais/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo
3.
Am J Nurs ; 122(12): 32-40, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36321823

RESUMO

ABSTRACT: Kaposi sarcoma is a tumor caused by Kaposi sarcoma herpesvirus, also known as human herpesvirus 8. Its occurrence is associated with an immunocompromised state. Kaposi sarcoma that occurs among people living with HIV (PLWH) is known as epidemic Kaposi sarcoma. Despite the decline in HIV-associated complications because of the introduction of combination antiretroviral therapy two decades ago, Kaposi sarcoma continues to affect PLWH worldwide. It affects young African American men more than other age and racial groups and can result in multiorgan dysfunction, leading to short-term and chronic debilitating symptoms as well as death. While some patients with epidemic Kaposi sarcoma are managed as outpatients, others may require higher levels of care and their acuity may fluctuate throughout their life span. Therefore, nurses, regardless of their specialty, may experience caring for a patient with epidemic Kaposi sarcoma at some point in their career. Learning about this condition and the needs of patients who have it will help nurses provide effective care. Here, the authors describe Kaposi sarcoma in general as well as the epidemiology, characteristics, and management of epidemic Kaposi sarcoma. They also describe specific nursing considerations in the care of PLWH who have the disease.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS , Infecções por HIV , Herpesvirus Humano 8 , Sarcoma de Kaposi , Masculino , Humanos , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/etiologia , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico
5.
Medicine (Baltimore) ; 101(43): e31310, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36316837

RESUMO

Kaposi sarcoma (KS) is a malignant vascular neoplasm caused by KS-associated herpesvirus (KSHV) infection. HIV plays a major role in KS pathogenesis. KS in HIV usually produces more malignant features than classic KS. Despite the close KS-HIV relationship, no study has reported the existence of HIV in KS tissue. We used ddPCR to detect HIV and KSHV in HIV+ KS samples and classic KS control. We verified KS cell types through immunohistochemistry and applied hypersensitive in situ hybridization (ISH) to detect HIV and KSHV in tumor cells. Furthermore, we co-stained samples with ISH and immunohistochemistry to identify HIV and KSHV in specific cell types. Regarding pathological stages, the KS were nodular (58.3%), plaque (33.3%), and patch (8.3%) tumors. Moreover, ddPCR revealed HIV in 58.3% of the KS samples. ISH revealed positive Pol/Gag mRNA signals in CD34 + tumor cells from HIV + patients (95.8%). HIV signals were absent in macrophages and other inflammatory cells. Most HIV + KS cells showed scattered reactive particles of HIV and KSHV. We demonstrated that HIV could infect CD34 + tumor cells and coexist with KSHV in KS, constituting a novel finding. We hypothesized that the direct KSHV-HIV interaction at the cellular level contributes to KS oncogenesis.


Assuntos
Infecções por HIV , Herpesvirus Humano 8 , Sarcoma de Kaposi , Neoplasias Cutâneas , Humanos , Sarcoma de Kaposi/complicações , Herpesvirus Humano 8/genética , Neoplasias Cutâneas/complicações , Infecções por HIV/complicações
6.
PLoS Pathog ; 18(11): e1010990, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36417478

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr (EBV) are gammaherpesviruses associated with multiple human malignancies. KSHV is the etiological agent of Kaposi's Sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). EBV is associated with Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL), nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). KSHV and EBV establish life-long latency in the human host with intermittent periods of lytic reactivation. Here, we identified a cellular factor named transforming growth factor-beta regulator 4 (TBRG4) that plays a role in the gammaherpesvirus lifecycle. We find that TBRG4, a protein that is localized to the mitochondria, can regulate lytic reactivation from latency of both KSHV and EBV. Knockdown of TBRG4 in cells latently infected with KSHV or EBV induced viral lytic gene transcription and replication. TBRG4 deficiency causes mitochondrial stress and increases reactive oxygen species (ROS) production. Treatment with a ROS scavenger decreased viral reactivation from latency in TBRG4-depleted cells. These data suggest that TBRG4 serves as a cellular repressor of KSHV and EBV reactivation through the regulation of ROS production.


Assuntos
Herpesvirus Humano 4 , Herpesvirus Humano 8 , Proteínas Mitocondriais , Latência Viral , Humanos , Herpesvirus Humano 4/fisiologia , Herpesvirus Humano 8/fisiologia , Proteínas Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Ligação a RNA/metabolismo
7.
Oncol Res Treat ; 45(11): 693-704, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36219975

RESUMO

BACKGROUND: Castleman disease (CD) encompasses a spectrum of rare disorders with characteristic histopathological features. Unicentric CD (UCD) is a benign, local hyperplasia of lymphoid tissue that is usually curable. Multicentric CD (MCD) manifests as a potentially life-threatening systemic disease with complex symptomatology which is mostly due to an overproduction of interleukin-6 (IL-6) or dysregulation of IL-6-related signaling pathways. From a therapeutic perspective, it is important to distinguish idiopathic MCD (iMCD) from those cases that are associated with the human herpesvirus-8 (HHV-8 + MCD). SUMMARY: During recent years, it has become increasingly clear that even HHV-8-negative MCD is not a homogeneous entity and that there are clinically distinct variants. International consensus guidelines for diagnosis and treatment have been developed for iMCD and UCD. KEY MESSAGES: We herein summarize recent advances in diagnosis, treatment, and novel insights into the pathogenesis of this disease.


Assuntos
Hiperplasia do Linfonodo Gigante , Herpesvirus Humano 8 , Humanos , Hiperplasia do Linfonodo Gigante/terapia , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Interleucina-6/uso terapêutico , Transdução de Sinais
8.
AIDS ; 36(14): 2067-2069, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36305185
9.
Viruses ; 14(10)2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36298642

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that is the causative agent of primary effusion lymphoma and Kaposi's sarcoma. In healthy carriers, KSHV remains latent, but a compromised immune system can lead to lytic viral replication that increases the probability of tumorigenesis. RIG-I-like receptors (RLRs) are members of the DExD/H box helicase family of RNA binding proteins that recognize KSHV to stimulate the immune system and prevent reactivation from latency. To determine if other DExD/H box helicases can affect KSHV lytic reactivation, we performed a knock-down screen that revealed DHX29-dependent activities appear to support viral replication but, in contrast, DDX24 and DDX49 have antiviral activity. When DDX24 or DDX49 are overexpressed in BCBL-1 cells, transcription of all lytic viral genes and genome replication were significantly reduced. RNA immunoprecipitation of tagged DDX24 and DDX49 followed by next-generation sequencing revealed that the helicases bind to mostly immediate-early and early KSHV mRNAs. Transfection of expression plasmids of candidate KSHV transcripts, identified from RNA pull-down, demonstrated that KSHV mRNAs stimulate type I interferon (alpha/beta) production and affect the expression of multiple interferon-stimulated genes. Our findings reveal that host DExD/H box helicases DDX24 and DDX49 recognize gammaherpesvirus transcripts and convey an antiviral effect in the context of lytic reactivation.


Assuntos
Herpesvirus Humano 8 , Interferon Tipo I , Sarcoma de Kaposi , Humanos , Antivirais/metabolismo , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/genética , Regulação Viral da Expressão Gênica , Herpesvirus Humano 8/fisiologia , Interferon Tipo I/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ativação Viral/genética , Latência Viral/genética , Replicação Viral/genética
10.
J Cell Mol Med ; 26(22): 5580-5589, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36209502

RESUMO

Primary human herpesvirus 8 (HHV8)-unrelated effusion large B-cell lymphoma (ELBCL) is recognized as a new clinical entity, but its pathogenesis and therapeutic strategies remain largely unknown. We have generated two mouse models with profuse lymphomatous effusions that resemble HHV8-unrelated ELBCL occurring in humans, by grafting the cell lines designated as Pell-1 and Pell-2. Using these in vivo models, we evaluated the potential role of vascular endothelial growth factor (VEGF) in the pathogenesis of HHV8-unrelated ELBCL. Both Pell-1 and Pell-2 cells consistently produced very high levels of VEGF in mice, in contrast to in vitro findings of relatively low VEGF production in culture medium by HHV8-unrelated ELBCL cells, especially Pell-1 cells. Conversely, returning Pell-1 cells grown in mice to culture medium markedly suppressed VEGF production to the original in vitro level. These findings suggest that the tumour microenvironment plays a role in the steady production of VEGF. We also found that the interaction between HHV8-unrelated ELBCL cells and peritoneal mesothelial cells increased the production of VEGF in vitro. Finally, we found that bevacizumab significantly suppressed effusion formation and lymphoma cell growth in both mouse models. These results suggest that bevacizumab is a rational approach to the treatment of HHV8-unrelated ELBCL.


Assuntos
Herpesvirus Humano 8 , Linfoma Difuso de Grandes Células B , Humanos , Camundongos , Animais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Fatores de Crescimento do Endotélio Vascular , Microambiente Tumoral
13.
J Virol ; 96(22): e0107322, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36300940

RESUMO

Tegument, which occupies the space between the nucleocapsid and the envelope, is a unique structure of a herpesvirion. Tegument proteins are major components of tegument and play critical roles in virus life cycle. Murine gammaherpesvirus 68 (MHV-68), a member of the gammaherpesvirus subfamily, is closely related to two human herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). We have previously shown that MHV-68 ORF33, conserved among all herpesviruses, encodes a tegument protein that is associated with intranuclear capsids and is essential for virion morphogenesis and egress. Another tegument protein ORF45, which is conserved only among gammaherpesviruses, also plays an essential role in virion morphogenesis of MHV-68. In this study, we investigated the underlying mechanism and showed that these two proteins colocalize and interact with each other during virus infection. We mapped the ORF33-interacting domain to the conserved carboxyl-terminal 23 amino acids (C23) of ORF45. Deletion of the C23 coding sequence in the context of viral genome abolished the production of infectious virions. Transmission electron microscopy results demonstrated that C23 of ORF45 are essential for virion tegumentation in the cytoplasm. We further mapped the ORF45-interacting domain to the N-terminal 17 amino acids (N17) of ORF33. Deletion of the N17 coding sequence in the context of viral genome also abolished production of infectious virions, and N17 of ORF33 are also essential for virion tegumentation in the cytoplasm. Taken together, our data strongly indicate that the interaction between ORF45 and ORF33 plays an essential role in cytoplasmic maturation of MHV-68 virions. IMPORTANCE A critical step in viral lytic replication is the assembly of progeny viral particles. Herpesviruses are important pathogens. A herpesvirus particle comprises, from inside to outside, four layers: DNA core, capsid, tegument, and envelope. The tegument layer contains dozens of virally encoded tegument proteins, which play critical roles in virus assembly. Murine gammaherpesvirus 68 (MHV-68) is a tumor-associated herpesvirus and is closely related to Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus. We previously found that the absence of either tegument protein ORF33 or ORF45 inhibits the translocation of nucleocapsids to the cytoplasm and blocks virion maturation, but the underlying mechanism remained unclear. Here, we showed that ORF33 interacts with ORF45. We mapped their interaction domains and constructed viral mutants with defects in ORF33-ORF45 interaction. Transmission electron microscopy data demonstrated that the assembly of these viral mutants in the cytoplasm is blocked. Our results indicate that ORF33-ORF45 interaction is essential for gammaherpesvirus replication.


Assuntos
Proteínas do Capsídeo , Proteínas Imediatamente Precoces , Rhadinovirus , Montagem de Vírus , Animais , Camundongos , Citoplasma/metabolismo , Herpesvirus Humano 4 , Herpesvirus Humano 8 , Rhadinovirus/genética , Rhadinovirus/fisiologia , Vírion/genética , Vírion/fisiologia , Replicação Viral , Proteínas do Capsídeo/metabolismo , Proteínas Imediatamente Precoces/metabolismo
14.
Biochem J ; 479(20): 2261-2278, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36305710

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is a carcinogenic virus that latently infects B cells and causes malignant tumors in immunocompromised patients. KSHV utilizes two viral E3 ubiquitin ligases, K3 and K5, in KSHV-infected cells to mediate the polyubiquitination-dependent down-regulation of several host membrane proteins involved in the immune system. Although K3 and K5 are members of the same family and have similar structural topologies, K3 and K5 have different substrate specificities. Hence, K5 may have a different substrate recognition mode than K3; however, the molecular basis of substrate recognition remains unclear. Here, we investigated the reason why human CD8α, which is known not to be a substrate for both K3 and K5, is not recognized by them, to obtain an understanding for molecular basis of substrate specificity. CD8α forms a disulfide-linked homodimer under experimental conditions to evaluate the viral ligase-mediated down-regulation. It is known that two interchain disulfide linkages in the stalk region between each CD8α monomer (Cys164-Cys164 and Cys181-Cys181) mediate homodimerization. When the interchain disulfide linkage of Cys181-Cys181 was eliminated, CD8α was down-regulated by K5 with a functional RING variant (RINGv) domain via polyubiquitination at the cytoplasmic tail. Aspartic acid, located at the stalk/transmembrane interface of CD8α, was essential for K5-mediated down-regulation of the CD8α mutant without a Cys181-Cys181 linkage. These results suggest that disulfide linkage near the stalk/transmembrane interface critically inhibits substrate targeting by K5. Accessibility to the extracellular juxtamembrane stalk region of membrane proteins may be important for substrate recognition by the viral ubiquitin ligase K5.


Assuntos
Herpesvirus Humano 8 , Proteínas Imediatamente Precoces , Humanos , Ubiquitina/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas de Membrana/metabolismo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Dissulfetos/metabolismo
15.
Viruses ; 14(10)2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36298740

RESUMO

Human herpesvirus 8 (HHV-8), the causative agent of Kaposi's sarcoma, multicentric Castleman's disease and primary effusion lymphoma, predominantly manifests in immunocompromised individuals. However, infection in immunocompetent individuals does occur. The prevalence of HHV-8 exposure in blood donors from non-endemic countries ranges between 1.2% and 7.3%. Nothing was known about the prevalence in Australian blood donors. Therefore, this study investigated the active and cumulative exposure of HHV-8 in this cohort. Plasma samples (n = 480) were collected from eastern Australian blood donors and were tested for HHV-8 DNA by qPCR, and for HHV-8 antibodies by two different ELISAs. Samples initially positive on either ELISA were retested in duplicate on both, and on a mock-coated ELISA. Any samples positive two or three out of the three times tested on at least one ELISA, and repeat negative on the mock-coated ELISA, were assigned as repeat positive. None of the 480 samples tested contained HHV-8 DNA. Serological testing revealed 28 samples (5.83%; 95% CI: 3.74-7.93%) had antibodies to HHV-8. There was no difference (p > 0.05) in seropositivity between sex or with increasing age. This is the first study to show serological evidence of cumulative HHV-8 exposure and no HHV-8 DNAemia within a select blood donor population in Australia. Our molecular and serological data is consistent with published results for blood donors residing in HHV-8 non-endemic countries, which shows the prevalence to be very low.


Assuntos
Hiperplasia do Linfonodo Gigante , Infecções por Herpesviridae , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Herpesvirus Humano 8/genética , Doadores de Sangue , Austrália/epidemiologia , Sarcoma de Kaposi/epidemiologia , Hiperplasia do Linfonodo Gigante/complicações
16.
Pathologica ; 114(5): 381-384, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36305025

RESUMO

Kaposi sarcoma is a low-grade mesenchymal tumor associated with human herpesvirus-8. Here we describe the case of a 37-year old woman, who underwent to kidney and liver transplant for congenital hepatic fibrosis and bilateral polycystic kidney, with successive immunosuppressive therapy. After 5 years from first transplant, she developed cutaneous, mucosal, pleural and nodal localizations of Kaposi sarcoma, without lung lesions. Because of an initial clinical presentation with an important nodal and pleural involvement, a diagnosis of a lymphoproliferative disease was suspected. Pathological examination of the pleural sample allowed to exclude lymphoproliferative neoplasia and was consistent with Kaposi sarcoma. Subsequently involvement of other sites was diagnosed as expression of diffuse disease. The interest of this case lays in the unusual clinical presentation which can lead to diagnostic pitfalls when evaluating pleural biopsies.


Assuntos
Herpesvirus Humano 8 , Sarcoma de Kaposi , Feminino , Humanos , Adulto , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/cirurgia , Terapia de Imunossupressão , Biópsia
17.
Viruses ; 14(10)2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36298850

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with vascular endothelial cell tumor, Kaposi's sarcoma (KS) and lymphoproliferative disorder, multicentric Castleman's disease (MCD), primary effusion lymphoma (PEL) and KSHV inflammatory cytokine syndrome (KICS). Dysregulation of proinflammatory cytokines is found in most KSHV associated diseases. However, little is known about the role of host microenvironment in the regulation of KSHV establishment in B cells. In the present study, we demonstrated that IFN-γ has a strong inhibitory effect on KSHV infection but only in a subset of tonsil-derived lymphocyte samples that are intrinsically more susceptible to infection, contain higher proportions of naïve B cells, and display increased levels of IRF1 and STAT1-pY701. The effect of IFN-γ in responsive samples was associated with increased frequencies of germinal center B cells (GCB) and decreased infection of plasma cells, suggesting that IFN-γ-mediated modulation of viral dynamics in GC can inhibit the establishment of KSHV infection.


Assuntos
Linfócitos B , Infecções por Herpesviridae , Herpesvirus Humano 8 , Interferon gama , Humanos , Síndrome de Imunodeficiência Adquirida/imunologia , Linfócitos B/imunologia , Hiperplasia do Linfonodo Gigante/imunologia , Citocinas/imunologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/imunologia , Interferon gama/imunologia , Sarcoma de Kaposi/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Suscetibilidade a Doenças/imunologia
18.
PLoS One ; 17(10): e0274058, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36282878

RESUMO

BACKGROUND: Since human herpesvirus 8 (HHV-8) infection may be underestimated and HHV-8 subtype circulation in Spain remains unknown, a molecular epidemiologic study is highly desirable. OBJECTIVES: This study aimed to analyse HHV-8 subtype diversity and their distribution in Spain. STUDY DESIGN: The study included 142 HHV-8 infected patients. A nested PCR was developed in order to permit Sanger sequencing of HHV-8 K1 ORF directly from clinical samples received at the CNM from 2013 to 2021. Phylogenetic characterization was performed. RESULTS: Genotypes A and C comprised 55.6% and 42.3% of strains. Regarding subtypes, 25.4% of strains were C3, 19.7% were A3, 14.1% were A5, and C2, A1, A4, C1, A2, C7 were 11.3%, 11.3%, 8.5%, 4.2%, 2.1% and 1.4%, respectively. Subtype E1, E2 and B1 were found in only one patient each (0.7%). The Madrid region accounted for 52.1% of patients and showed a significantly different subtype distribution compared to the others (P = 0.018). Subtypes B1, E1, and E2 were observed to appear sporadically, although overall genotypes A and subtype C3 remained the most frequent and unwavering. Subtype A3 presented the highest diversity as displayed by the highest number of clusters in phylogenetic analysis. Non-significant differences in viral loads between genotypes were found, but significantly higher viral loads in subtype C2 compared to subtype C3 was found, while no significant subtype differences were observed between subtypes within genotype A. Infections with HHV-8 were detected in 94 (66.2%) patients without KS and compared to patients with KS non-significant differences in subtype distribution were found. CONCLUSIONS: Subtype prevalence and regional distribution followed a similar pattern compared to other western European countries. Our study is the first to report HHV-8 subtypes E1 and E2 circulating in Europe that might be reflective of migration of population from Caribbean countries. Our study suggests that infection by HHV-8 is underestimated, and wider screening should be recommended for risk groups.


Assuntos
Síndrome de Imunodeficiência Adquirida , Infecções por Herpesviridae , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/genética , Epidemiologia Molecular , Filogenia , Espanha/epidemiologia , Herpesvirus Humano 8/genética , Síndrome de Imunodeficiência Adquirida/epidemiologia , Infecções por Herpesviridae/epidemiologia , Retroviridae/genética , DNA Viral/genética
19.
Viruses ; 14(9)2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36146679

RESUMO

Beyond their pulmonary disease, many COVID-19 patients experience a complex constellation of characteristics, including hyperinflammatory responses, autoimmune disorders, and coagulopathies. However, the pathogenesis of these aspects of COVID-19 is obscure. More than 90% of people are latently infected with the lymphotropic herpesviruses Epstein-Barr Virus (EBV) and/or Human Herpesvirus-6 (HHV-6). Some of the inflammatory features of COVID-19 resemble clinical syndromes seen during EBV and HHV-6 infection, and these latent viruses can be reactivated by inflammatory mediators. We hypothesized that EBV and HHV-6 reactivation might be a common feature of early COVID-19, particularly in patients with more inflammation. We tested for EBV and HHV-6 reactivation in 67 patients acutely hospitalized with COVID-19 using previously validated quantitative PCR assays on the plasma. In our cohort, we found that 15/67 (22.4%) patients had detectable EBV and 3/67 (4.5%) had detectable HHV-6. This frequency of activation is somewhat more than the frequency reported for some healthy cohorts, such as blood donors and other healthy control cohorts. There was no association between EBV or HHV-6 and markers indicative of more inflammatory disease. We conclude that EBV and HHV-6 activation at about day 7 of hospitalization occurred in a modest fraction of our cohort of COVID-19 patients and was not associated with high levels of inflammation. In the modest fraction of patients, EBV and HHV-6 reactivation could contribute to some features of acute disease and pre-disposition to post-acute sequelae in a subset of patients.


Assuntos
COVID-19 , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 6 , Herpesvirus Humano 8 , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/fisiologia , Herpesvirus Humano 6/fisiologia , Humanos , Inflamação , Mediadores da Inflamação
20.
Viruses ; 14(9)2022 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-36146816

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) protein ORF45 is a virion-associated tegument protein that is unique to the gammaherpesvirus family. Generation of KSHV ORF45-knockout mutants and their subsequent functional analyses have permitted a better understanding of ORF45 and its context-specific and vital role in the KSHV lytic cycle. ORF45 is a multifaceted protein that promotes infection at both the early and late phases of the viral life cycle. As an immediate-early protein, ORF45 is expressed within hours of KSHV lytic reactivation and plays an essential role in promoting the lytic cycle, using multiple mechanisms, including inhibition of the host interferon response. As a tegument protein, ORF45 is necessary for the proper targeting of the viral capsid for envelopment and release, affecting the late stage of the viral life cycle. A growing list of ORF45 interaction partners have been identified, with one of the most well-characterized being the association of ORF45 with the host extracellular-regulated kinase (ERK) p90 ribosomal s6 kinase (RSK) signaling cascade. In this review, we describe ORF45 expression kinetics, as well as the host and viral interaction partners of ORF45 and the significance of these interactions in KSHV biology. Finally, we discuss the role of ORF45 homologs in gammaherpesvirus infections.


Assuntos
Herpesvirus Humano 8 , Animais , Linhagem Celular , Regulação Viral da Expressão Gênica , Herpesvirus Humano 8/fisiologia , Interferons/metabolismo , Estágios do Ciclo de Vida , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Replicação Viral/fisiologia
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