Showing papers on "Gammaherpesvirinae published in 2022"

Mitochondrial protein, TBRG4, modulates KSHV and EBV reactivation from latency

Abstract: 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.

IKKα-Mediated Noncanonical NF-κB Signaling Is Required To Support Murine Gammaherpesvirus 68 Latency In Vivo

Abstract: The latency programs of the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are associated with B cell lymphomas. It is critical to understand the signaling pathways that are used by gammaherpesviruses to establish and maintain latency in primary B cells. ABSTRACT Noncanonical NF-κB signaling is activated in B cells via the tumor necrosis factor (TNF) receptor superfamily members CD40, lymphotoxin β receptor (LTβR), and B-cell-activating factor receptor (BAFF-R). The noncanonical pathway is required at multiple stages of B cell maturation and differentiation, including the germinal center reaction. However, the role of this pathway in gammaherpesvirus latency is not well understood. Murine gammaherpesvirus 68 (MHV68) is a genetically tractable system used to define pathogenic determinants. Mice lacking the BAFF-R exhibit defects in splenic follicle formation and are greatly reduced for MHV68 latency. We report a novel approach to disrupt noncanonical NF-κB signaling exclusively in cells infected with MHV68. We engineered a recombinant virus that expresses a dominant negative form of IκB kinase α (IKKα), named IKKα-SA, with S176A and S180A mutations that prevent phosphorylation by NF-κB-inducing kinase (NIK). We controlled for the transgene insertion by introducing two all-frame stop codons into the IKKα-SA gene. The IKKα-SA mutant but not the IKKα-SA.STOP control virus impaired LTβR-mediated activation of NF-κB p52 upon fibroblast infection. IKKα-SA expression did not impact replication in primary fibroblasts or in the lungs of mice following intranasal inoculation. However, the IKKα-SA mutant was severely defective in the colonization of the spleen and in the establishment of latency compared to the IKKα-SA.STOP control and wild-type (WT) MHV68 at 16 days postinfection (dpi). Reactivation was undetectable in splenocytes infected with the IKKα-SA mutant, but reactivation in peritoneal cells was not impacted by IKKα-SA. Taken together, the noncanonical NF-κB signaling pathway is essential for the establishment of latency in the secondary lymphoid organs of mice infected with the murine gammaherpesvirus pathogen MHV68. IMPORTANCE The latency programs of the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are associated with B cell lymphomas. It is critical to understand the signaling pathways that are used by gammaherpesviruses to establish and maintain latency in primary B cells. We used a novel approach to block noncanonical NF-κB signaling only in the infected cells of mice. We generated a recombinant virus that expresses a dominant negative mutant of IKKα that is nonresponsive to upstream activation. Latency was reduced in a route- and cell type-dependent manner in mice infected with this recombinant virus. These findings identify a significant role for the noncanonical NF-κB signaling pathway that might provide a novel target to prevent latent infection of B cells with oncogenic gammaherpesviruses.

[Epstein-Barr virus (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) in Kalmyks and Slavs living in Russia: virus types, LMP1 oncogene variants, and malignancies].

Abstract: INTRODUCTION The discovery of the Epstein-Barr virus types (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) (EBV) - EBV-1 and EBV-2, which have different transforming abilities in vitro, stimulated the study of their prevalence in populations in order to elucidate the relationship with malignant neoplasms.The aims of the work are to study the prevalence of EBV-1 and EBV-2 among representatives of 2 ethnic groups of Russia, Kalmyks and Slavs, sequencing analysis of the LMP1 oncogene in virus isolates, and analysis of the correlation between virus types and the incidence of certain forms of tumors. MATERIALS AND METHODS DNA samples were isolated from the biological material of oral swabs obtained from ethnic Kalmyks of the Republic of Kalmykia (RK) (n = 50) and Slavs, residents of the Moscow Region (MR) (n = 40). DNA samples were used to amplify EBV DNA, followed by determination of its concentration per 1 cell of washout, amplification of the LMP1 oncogene in viral samples, their sequencing, and determination of LMP1 protein variants. RESULTS It has been established that with the same burden of EBV among representatives of both ethnic groups in the Kalmyk group, the ratio of persons infected with transforming and non-transforming types of the virus was almost the same (EBV-1 - 51%; and EBV-2 - 49%). Meanwhile, in the group of Slavs the transforming EBV-1 type virus dominated (80.6%). The predominance of EBV-1 type in representatives of the Slavs correlated with increased incidence of certain forms of tumors in the population of the MR when compared with similar values in the population of the RK, where both types of the virus were prevalent. Differences between the compared rates of cancer incidence were not statistically significant. Analysis of viral isolates showed a similar set of LMP1 variants in both ethnic groups. CONCLUSION In order to establish the influence of EBV types on the incidence of malignant tumors, additional studies involving representatives of various ethnic groups from different geographical regions are needed.

Herpesvirus infections in adenoids in patients with chronic adenotonsillar disease

Abstract: Adenoids and tonsils have gained interest as a new in vivo model to study local immune functions and virus reservoirs. Especially herpesviruses are interesting because their prevalence and persistence in local lymphoid tissue are incompletely known. Our aim was to study herpesvirus and common respiratory virus infections in nonacutely ill adenotonsillar surgery patients. Adenoid and/or palatine tonsil tissue and nasopharyngeal aspirate (NPA) samples were collected from elective adenoidectomy (n = 45) and adenotonsillectomy (n = 44) patients (median age: 5, range: 1–20). Real‐time polymerase chain reaction was used to detect 22 distinct viruses from collected samples. The overall prevalence of herpesviruses was 89% and respiratory viruses 94%. Human herpesviruses 6 (HHV6), 7 (HHV7), and Epstein–Barr virus (EBV) were found, respectively, in adenoids (33%, 26%, 25%), tonsils (45%, 52%, 23%), and NPA (46%, 38%, 25%). Copy numbers of the HHV6 and HHV7 genome were significantly higher in tonsils than in adenoids. Patients with intra‐adenoid HHV6 were younger than those without. Detection rates of EBV and HHV7 showed agreement between corresponding sample types. This study shows that adenoid and tonsil tissues commonly harbor human herpes‐ and respiratory viruses, and it shows the differences in virus findings between sample types.

EBV Association with Lymphomas and Carcinomas in the Oral Compartment

Abstract: Epstein–Barr virus (EBV) is an oncogenic human herpesvirus infecting approximately 90% of the world’s population. The oral cavity serves a central role in the life cycle, transmission, and pathogenesis of EBV. Transmitted to a new host via saliva, EBV circulates between cellular compartments within oral lymphoid tissues. Epithelial cells primarily support productive viral replication, while B lymphocytes support viral latency and reactivation. EBV infections are typically asymptomatic and benign; however, the latent virus is associated with multiple lymphomas and carcinomas arising in the oral cavity. EBV association with cancer is complex as histologically similar cancers often test negative for the virus. However, the presence of EBV is associated with distinct features in certain cancers. The intrinsic ability of EBV to immortalize B-lymphocytes, via manipulation of survival and growth signaling, further implicates the virus as an oncogenic cofactor. A distinct mutational profile and burden have been observed in EBV-positive compared to EBV-negative tumors, suggesting that viral infection can drive alternative pathways that converge on oncogenesis. Taken together, EBV is also an important prognostic biomarker that can direct alternative therapeutic approaches. Here, we discuss the prevalence of EBV in oral malignancies and the EBV-dependent mechanisms associated with tumorigenesis.

The role of Herpesviridae infection in the progression of comorbid somatic pathology

Abstract: Мета роботи: визначити особливості клітинної та гуморальної ланок імунної системи у хворих на хронічне обструктивне захворювання легень (ХОЗЛ) груп В та С, GOLD 2–3, які мають ознаки метаболічного синдрому (МС), із наявністю ознак інфікування вірусами групи Herpesviridae. Матеріали та методи. Були обстежені 42 хворі на ХОЗЛ груп В та С, GOLD 2–3, поєднане із МС. 18 осіб мали поєд­нання ХОЗЛ та МС і були інфіковані вірусами Herpesviridae. Середній вік пацієнтів становив 51,3 ± 4,2 роки. У групу порівняння ввійшли 24 пацієнти з ХОЗЛ та МС без герпесвірусної інфекції. Усім хворим було проведене визначення антигенів вірусу простого герпесу (ВПГ) І типу та цитомегаловірусу (ЦМВ) у крові та слині, титру специфічних IgG- та IgM-антитіл до ВПГ І типу та ЦМВ, комплексне імунологічне обстеження з дослідженням показників клітинної та гуморальної ланок імунної системи, цитокінового статусу. Результати. При дослідженні активності вірусів родини герпесу в крові пацієнтів основної групи не було виявлено активної реплікації вірусів ВПГ 1-го типу та ЦМВ, а в слині в 15 хворих (83,3 %) була виявлена активна реплікація ВПГ 1-го типу, а у 12 осіб (66,7 %) — ЦМВ. У всіх пацієнтів основної групи відмічався тяжкий перебіг герпесвірусної інфекції з частотою загострень більше 6 разів на рік. В імунологічному статусі хворих основної групи спостерігалися імунодефіцит переважно Т-клітинної ланки імунної системи та NK-клітин, значне підвищення відносної кількості Т- та В-лімфоцитів із раннім та пізнім маркерами активації на тлі автоімунних проявів та запальних змін у периферичній крові. Висновки. Наявність хронічної персистуючої інфекції ВПГ 1-го типу та ЦМВ обумовлює тяжкий перебіг ХОЗЛ, поєднаного з МС, індукує розвиток інфекційних загострень ХОЗЛ та більш виражені прояви системного запалення при атеросклерозі як морфологічному субстраті МС.

Comparaison du profil d’expression des immunecheckpoints dans les lymphomes B diffus à grandes cellules NOS, EBV+ et EBV− : impact sur le pronostic

Abstract: Peu de publications ont été réalisées sur l’expression des immunecheckpoints (PD1-et PD-L1) par les cellules lymphoïdes tumorales des lymphomes B diffus à grandes cellules (LBDGC) NOS EBV+ et EBV-. Caractérisation et comparaison du profil d’expression de PD1, PD-L1 par les cellules lymphoïdes tumorales des LBDGC NOS EBV+ et EBV−. Nous avons comparé 78 patients LBDGC EBV− NOS dont 67 de phénotype ABC et 11 GCB avec 13 patients LBDGC EBV+ ABC suivis et traités par R-CHOP sur une période de 44 mois. Nous avons estimé le pourcentage d’expression par les cellules lymphoïdes tumorales de PD-L1 (CAL10) avec un cut off de 30 %, et PD-1(NAT 105) avec un cut off de 5 %. Dans notre série, il a été observé une différence significative entre les deux groupes sur l’expression de PD-L1 par les cellules lymphomateuses p < 0,0001. Cette expression a été retrouvée dans 100 % des LBDGC EBV+ et dans 24,4 % des LBDGC EBV−. Le PD-1 n’a pas montré de différence significative entre les deux groupes p = 0,261. Il a été exprimé par 15,4 % des LBDGC EBV+ et 6,4 % des LBDGC EBV. L’expression de PD-L1 a été corrélée à une mauvaise réponse au traitement et une survie inférieure p = 0,006. Nous avons également noté une différence significative entre les deux groupes sur la réponse au traitement R-CHOP ( p = 0,01) et sur le taux de survie entre les LBDGC EBV+ et EBV-, Log Rank (Mantel-Cox) p = 0,0001. La fréquence d’expression de PD-L1 dans les LBDGC est de l’ordre de 20 % à 30 %, mais dépend du seuil de positivité retenu et du compartiment cellulaire analysé, tumoral ou environnemental. Nos résultats sont concordants avec les données de la littérature avec un seuil de positivité à 30 %. Elles sont également concordantes sur la fréquence plus élevée de cellules tumorales PD-L1+ dans les LBDGC de phénotype ABC ainsi que l’association forte entre l’expression de PD-L1 et la présence d’EBV. De rares observations ont cependant décrit dans un faible pourcentage de cas, l’expression de PD-1 à la surface des cellules lymphomateuses et la possible co-expression de PD-1 et de PD-L1 par les mêmes cellules tumorales. Les résultats restent controversés. Notre étude démontre que l’expression de PD-L1 par les cellules lymphoïdes tumorales est un facteur prédictif de la réponse thérapeutique et la survie ; en plus du statut EBV dans les LBDGC.