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HIV-1 衣壳作为纳米级别的逆转录反应容器。

The HIV-1 capsid serves as a nanoscale reaction vessel for reverse transcription.

机构信息

Department of Pathology, Microbiology, and Immunology and Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Division of Infectious Disease, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.

出版信息

PLoS Pathog. 2024 Sep 3;20(9):e1011810. doi: 10.1371/journal.ppat.1011810. eCollection 2024 Sep.

Abstract

The viral capsid performs critical functions during HIV-1 infection and is a validated target for antiviral therapy. Previous studies have established that the proper structure and stability of the capsid are required for efficient HIV-1 reverse transcription in target cells. Moreover, it has recently been demonstrated that permeabilized virions and purified HIV-1 cores undergo efficient reverse transcription in vitro when the capsid is stabilized by addition of the host cell metabolite inositol hexakisphosphate (IP6). However, the molecular mechanism by which the capsid promotes reverse transcription is undefined. Here we show that wild type HIV-1 virions can undergo efficient reverse transcription in vitro in the absence of a membrane-permeabilizing agent. This activity, originally termed "natural endogenous reverse transcription" (NERT), depends on expression of the viral envelope glycoprotein during virus assembly and its incorporation into virions. Truncation of the gp41 cytoplasmic tail markedly reduced NERT activity, suggesting that gp41 licenses the entry of nucleotides into virions. By contrast to reverse transcription in permeabilized virions, NERT required neither the addition of IP6 nor a mature capsid, indicating that an intact viral membrane can substitute for the function of the viral capsid during reverse transcription in vitro. Collectively, these results demonstrate that the viral capsid functions as a nanoscale container for reverse transcription during HIV-1 infection.

摘要

病毒衣壳在 HIV-1 感染过程中发挥着关键作用,是抗病毒治疗的有效靶点。先前的研究已经证实,衣壳的适当结构和稳定性是 HIV-1 在靶细胞中有效逆转录所必需的。此外,最近的研究表明,当衣壳通过添加宿主细胞代谢物肌醇六磷酸(IP6)稳定时,通透病毒粒子和纯化的 HIV-1 核心在体外可有效进行逆转录。然而,衣壳促进逆转录的分子机制尚不清楚。在这里,我们表明野生型 HIV-1 病毒粒子在没有膜透化剂的情况下可在体外有效进行逆转录。该活性最初被称为“天然内源性逆转录”(NERT),依赖于病毒组装过程中包膜糖蛋白的表达及其掺入病毒粒子中。gp41 细胞质尾巴的截断显著降低了 NERT 活性,表明 gp41 许可核苷酸进入病毒粒子。与通透病毒粒子中的逆转录不同,NERT 既不需要添加 IP6,也不需要成熟的衣壳,表明完整的病毒膜可在体外逆转录过程中替代病毒衣壳的功能。总之,这些结果表明,病毒衣壳在 HIV-1 感染过程中充当逆转录的纳米级容器。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4f3/11398657/90a669890f98/ppat.1011810.g001.jpg

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