Glycoproteins gM and gN are indispensable factors for rhesus macaque rhadinovirus replication and spread but can be reconstituted by KSHV chimeras.

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-25 DOI:10.1128/jvi.01922-24
Gavin Golas, Byung S Park, Scott W Wong
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引用次数: 0

Abstract

Rhesus macaque rhadinovirus (RRV) is a primate gamma-2 herpesvirus (rhadinovirus) closely related to Kaposi sarcoma-associated herpesvirus (KSHV), the human oncovirus that causes Kaposi sarcoma. Like other herpesviruses, KSHV and RRV encode numerous envelope glycoproteins involved in cell attachment, entry, as well as assembly and release of progeny virions from infected cells. Two glycoproteins postulated to form a complex and reported to be virus-neutralizing targets are glycoproteins M (gM) and N (gN). To investigate gM and gN in rhadinovirus infection, we utilized infectious and pathogenic bacterial artificial chromosomes (BAC). RRV BACmids with nonsense mutations introduced into gM or gN did not yield an infectious virus. However, when gM or gN of RRV were exchanged for gM or gN from KSHV, each of the KSHV-chimeric RRV BACmids restored virus replication and infectious spread. Interestingly, we also discovered that the substitution of KSHVgM into the RRV BACmid was associated with attenuation in viral spread, an effect that was not countered by a double-chimeric virus. In contrast, the substitution of RRV gN into a KSHV BACmid negatively affected the assembly of KSHV, independent of gM/gN complex formation. Therefore, here, we revealed that in KSHV and RRV, gM and gN are interchangeable, contribute to crucial functions for viral assembly and spread, and have evolved in a virus-specific manner. Although more research is needed to define the roles of gM and gN, our work establishes the first glycoprotein-chimeric viruses for KSHV and RRV, which can now be used to corroborate gM/gN as targets for a cancer vaccine.IMPORTANCEKaposi sarcoma (KS) is a human cancer caused by KSHV and is one of the most frequently occurring cancers in HIV/AIDS patients, as well as in regions where KSHV is endemic. In this report, we have constructed and authenticated the first KSHV glycoprotein-encoding chimeric viruses for evaluations in the RRV/rhesus macaque model and have also uncovered fundamental roles for the glycoproteins gM and gN. Our work is significant by successfully bridging the human-specific, species barrier that has previously restricted preclinical evaluations of the KSHV glycoproteins as vaccine targets in vivo. Although there is no KSHV-specific animal model that is widely used, these KSHV-chimeric viruses may be useful as tools to guide future vaccine design and strategy as vaccine candidates progress toward clinical trials.

糖蛋白gM和gN是恒河猴病毒复制和传播不可缺少的因子,但可以通过KSHV嵌合体重组。
恒河猴横纹肌病毒(RRV)是一种灵长类γ -2疱疹病毒(横纹肌病毒),与卡波西肉瘤相关疱疹病毒(KSHV)密切相关,后者是引起卡波西肉瘤的人类癌病毒。与其他疱疹病毒一样,KSHV和RRV编码许多包膜糖蛋白,这些包膜糖蛋白参与细胞附着、进入以及从感染细胞中组装和释放子代病毒粒子。两种糖蛋白被认为可以形成一种复合物,并被报道为病毒中和的靶标:糖蛋白M (gM)和N (gN)。利用感染性和致病性细菌人工染色体(BAC)研究了gM和gN在横纹肌病毒感染中的作用。将无义突变的RRV BACmids引入gM或gN中不会产生感染性病毒。然而,当RRV的gM或gN与KSHV的gM或gN交换时,每个KSHV嵌合的RRV BACmids都恢复了病毒的复制和传染性传播。有趣的是,我们还发现KSHVgM取代RRV BACmid与病毒传播的衰减有关,这种效应不会被双嵌合病毒抵消。相反,将RRV gN替换成KSHV BACmid会对KSHV的组装产生负面影响,而不依赖于gM/gN复合物的形成。因此,我们发现在KSHV和RRV中,gM和gN是可互换的,对病毒组装和传播起关键作用,并以病毒特异性的方式进化。虽然需要更多的研究来确定gM和gN的作用,但我们的工作建立了KSHV和RRV的第一个糖蛋白嵌合病毒,现在可以用来证实gM/gN作为癌症疫苗的靶点。卡波西肉瘤(KS)是一种由KSHV引起的人类癌症,是HIV/AIDS患者以及KSHV流行地区最常见的癌症之一。在本报告中,我们构建并鉴定了第一个编码KSHV糖蛋白的嵌合病毒,用于RRV/恒河猴模型的评估,并揭示了糖蛋白gM和gN在RRV/恒河猴模型中的基本作用。我们的工作具有重要意义,因为它成功地跨越了人类特异性的物种障碍,这种障碍以前限制了KSHV糖蛋白作为体内疫苗靶点的临床前评估。虽然目前还没有广泛使用的kshv特异性动物模型,但随着候选疫苗进入临床试验阶段,这些kshv嵌合病毒可能是指导未来疫苗设计和策略的有用工具。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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