A Conserved Tryptophan in the Envelope Cytoplasmic Tail Regulates HIV-1 Assembly and Spread.
A Conserved Tryptophan in the Envelope Cytoplasmic Tail Regulates HIV-1 Assembly and Spread.
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DOI：
10.3390/v14010129
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发表时间：
2022-01-12
期刊：
影响因子：
--
通讯作者：
Jolly C
中科院分区：
文献类型：
--
作者：
Snetkov X;Haider T;Mesner D;Groves N;van Engelenburg SB;Jolly C
HIV-1包膜（Env）是病毒感染性、嗜性和T细胞间传播的重要决定因素。慢病毒Env含有异常长的150个氨基酸的胞质尾（EnvCT），但EnvCT及其内许多保守结构域的功能在很大程度上仍未得到表征。在这里，我们在EnvCT的LLP-2 α螺旋中的位置757（W757）处鉴定了高度保守的色氨酸基序，其为HIV-1复制和在T细胞之间传播的关键决定因素。在这个位置的丙氨酸取代通过阻止Env和Gag募集到细胞-细胞接触位点，抑制病毒学突触（VS）形成和传播感染，有效抑制HIV-1细胞-细胞传播（HIV-1传播的主要模式）。单分子追踪和超分辨率成像显示，W757突变使Env在质膜中的扩散失调并增加Env迁移率。对Env功能的进一步分析表明，W757也是Env融合和感染性所需的，其与减少的VS形成一起导致病毒传播的有效缺陷。值得注意的是，W757位于EnvCT的一个区域内，最近被证明是Env的支撑基板。我们的数据支持这样一种模型，其中W757在调节Env生物学、调节其在病毒组装位点的时间和空间募集以及调节Env胞外域的固有融合性方面发挥关键作用，从而支持高效的HIV-1复制和传播。
The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains within it remain largely uncharacterised. Here, we identified a highly conserved tryptophan motif at position 757 (W757) in the LLP-2 alpha helix of the EnvCT as a key determinant for HIV-1 replication and spread between T cells. Alanine substitution at this position potently inhibited HIV-1 cell–cell spread (the dominant mode of HIV-1 dissemination) by preventing recruitment of Env and Gag to sites of cell–cell contact, inhibiting virological synapse (VS) formation and spreading infection. Single-molecule tracking and super-resolution imaging showed that mutation of W757 dysregulates Env diffusion in the plasma membrane and increases Env mobility. Further analysis of Env function revealed that W757 is also required for Env fusion and infectivity, which together with reduced VS formation, result in a potent defect in viral spread. Notably, W757 lies within a region of the EnvCT recently shown to act as a supporting baseplate for Env. Our data support a model in which W757 plays a key role in regulating Env biology, modulating its temporal and spatial recruitment to virus assembly sites and regulating the inherent fusogenicity of the Env ectodomain, thereby supporting efficient HIV-1 replication and spread.
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影响因子：
32.4
作者：
Falkowska, Emilia;Le, Khoa M.;Ramos, Alejandra;Doores, Katie J.;Lee, Jeong Hyun;Blattner, Claudia;Ramirez, Alejandro;Derking, Ronald;van Gils, Marit J.;Liang, Chi-Hui;Mcbride, Ryan;von Bredow, Benjamin;Shivatare, Sachin S.;Wu, Chung-Yi;Chan-Hui, Po-Ying;Liu, Yan;Feizi, Ten;Zwick, Michael B.;Koff, Wayne C.;Seaman, Michael S.;Swiderek, Kristine;Moore, John P.;Evans, David;Paulson, James C.;Wong, Chi-Huey;Ward, Andrew B.;Wilson, Ian A.;Sanders, Rogier W.;Poignard, Pascal;Burton, Dennis R.
通讯作者：
Burton, Dennis R.
影响因子：
5.4
作者：
Groppelli E;Starling S;Jolly C
通讯作者：
Jolly C
影响因子：
5.4
作者：
Berlioz-Torrent, C;Shacklett, BL;Benarous, R
通讯作者：
Benarous, R
影响因子：
5.4
作者：
Kalia, V;Sarkar, S;Montelaro, RC
通讯作者：
Montelaro, RC
影响因子：
5.6
作者：
Checkley MA;Luttge BG;Freed EO
通讯作者：
Freed EO