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将 HIV-1 颗粒感染性扭成结:罗卡酰胺通过改变 Gag-基因组 RNA 相互作用抑制 HIV-1 复制。

Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction.

机构信息

Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.

Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USA.

出版信息

Viruses. 2024 Sep 23;16(9):1506. doi: 10.3390/v16091506.

Abstract

Our examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4 T cells and three cell systems. HIV-1 attenuation by low-nM RocA doses was associated with reduced viral particle formation without a marked decrease in Gag production. Rather, the co-localization of Gag and HIV-1 genomic RNA (gRNA) assemblies was impaired by RocA treatment in a reversible fashion. Ribonucleoprotein (RNP) immunoprecipitation studies recapitulated the loss of Gag-gRNA assemblies upon RocA treatment. Parallel biophysical studies determined that neither RocA nor eIF4A1 independently affected the ability of Gag to interact with viral RNA, but together, they distorted the structure of the HIV-1 RNP visualized by electron microscopy. Taken together, several lines of evidence indicate that RocA induces stable binding of eIF4A1 onto the viral RNA genome in a manner that interferes with the ordered assembly of Gag along Gag-gRNA assemblies required to generate infectious virions.

摘要

我们研究了 RNA 解旋酶对 HIV-1 蛋白产生和颗粒组装的影响,发现 Rocaglamide(RocA)是 eIF4A1 功能的已知调节剂,能够抑制原代 CD4 T 细胞和三种细胞系中的 HIV-1 复制。低纳摩尔 RocA 剂量引起的 HIV-1 衰减与病毒颗粒形成减少有关,而不是 Gag 产生明显减少。相反,RocA 处理以可逆的方式损害了 Gag 和 HIV-1 基因组 RNA(gRNA)组装的共定位。核糖核蛋白(RNP)免疫沉淀研究再现了 RocA 处理后 Gag-gRNA 组装体的丢失。平行的生物物理研究表明,RocA 和 eIF4A1 都不能独立影响 Gag 与病毒 RNA 相互作用的能力,但它们共同扭曲了电子显微镜观察到的 HIV-1 RNP 的结构。综上所述,有几条证据表明 RocA 以一种干扰 Gag 沿着 Gag-gRNA 组装体有序组装的方式诱导 eIF4A1 稳定结合到病毒 RNA 基因组上,从而生成感染性病毒颗粒。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/baf1/11437399/a2e7ba451948/viruses-16-01506-g001.jpg

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