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Disruption of the Interaction between ORF33 and the Conserved Carboxyl-Terminus of ORF45 Abolishes Progeny Virion Production of Kaposi Sarcoma-Associated Herpesvirus
Viruses ( IF 5.818 ) Pub Date : 2021-09-14 , DOI: 10.3390/v13091828
Joseph Gillen 1 , Fanxiu Zhu 2
Affiliation  

The Open Reading Frame 45 (ORF45) of Kaposi sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus-specific, immediate-early, tegument protein required for efficient viral replication and virion production. We have previously shown that ORF45 interacts with the conserved herpesviral protein ORF33 through the highly conserved C-terminal 19 amino acids (C19) of ORF45. Because the deletion of C19 abolished ORF33 accumulation and viral production, we reasoned that this interaction could be critical for viral production and explored as an antiviral target for gammaherpesviruses. In this article, we characterize this interaction in further detail, first by revealing that this interaction is conserved among gammaherpesviruses, then by identifying residues in C19 critical for its interaction with, and stabilization of, ORF33. More importantly, we show that disruption of the interaction, either by mutating key residues (W403A or W405A) in C19 or by using competing cell penetration peptide TAT-C19, dramatically reduce the yield of KSHV progeny viruses. Our results not only reveal critical roles of this interaction to viral production but also provide a proof of concept for targeting the ORF33-ORF45 interaction as a novel antiviral strategy against KSHV and other gammaherpesviruses.

中文翻译:

破坏 ORF33 和 ORF45 保守羧基末端之间的相互作用会消除卡波西肉瘤相关疱疹病毒的子代病毒粒子产生

卡波西肉瘤相关疱疹病毒 (KSHV) 的开放阅读框 45 (ORF45) 是一种伽玛疱疹病毒特异性的、即早期的被膜蛋白,是有效病毒复制和病毒颗粒产生所需的。我们之前已经证明ORF45通过ORF45高度保守的C端19个氨基酸(C19)与保守的疱疹病毒蛋白ORF33相互作用。由于 C19 的删除消除了 ORF33 的积累和病毒的产生,因此我们推断这种相互作用可能对病毒的产生至关重要,并作为伽马疱疹病毒的抗病毒靶点进行了探索。在本文中,我们更详细地描述了这种相互作用,首先揭示了这种相互作用在伽马疱疹病毒中是保守的,然后通过鉴定 C19 中对其与 ORF33 相互作用和稳定至关重要的残基。更重要的是,我们表明,通过突变 C19 中的关键残基(W403A 或 W405A)或通过使用竞争性细胞穿透肽 TAT-C19 来破坏相互作用,可显着降低 KSHV 子代病毒的产量。我们的结果不仅揭示了这种相互作用对病毒产生的关键作用,而且还为以 ORF33-ORF45 相互作用作为针对 KSHV 和其他伽马疱疹病毒的新型抗病毒策略提供了概念证明。
更新日期:2021-09-14
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