HIV protease: late action to prevent immune detection.
HIV protease: late action to prevent immune detection.
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HIV蛋白酶：防止免疫检测的后期行动。
DOI：
10.1038/s41392-021-00588-2
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发表时间：
2021-04-16
影响因子：
39.3
通讯作者：
Kirchhoff F
中科院分区：
文献类型：
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作者：
Sparrer KMJ;Kirchhoff F
Wang及其同事最近在Science 1上发表的一项研究表明，HIV-1蛋白酶的过早激活导致感染的巨噬细胞和CD 4 + T细胞的半胱天冬酶激活和募集结构域8（CARD 8）炎症介导的焦亡（图1）。这些发现可能有助于改进旨在消除HIV-1重新激活后潜伏病毒库的方法。大多数入侵的病毒病原体会触发先天免疫系统，通常会被迅速控制并最终消除。细胞通过所谓的模式识别受体（PRR）感知病毒入侵者，该受体能够检测病原体相关分子模式（PAMP），从而区分自我和非自我。在许多情况下，这些模式是显示病原体特异性结构或出现在细胞中错误位置的病毒核酸。最终，PRR通过其各自的配体的活化导致各种抗病毒信号传导级联的诱导，其中包括炎性体。然而，HIV-1，艾滋病的主要病原体，以其逃避先天免疫感应的能力而闻名。例如，越来越多的证据表明，病毒衣壳在病毒进入时基本上保持完整，从而保护逆转录（RT）过程的中间体免受模式识别。[2]整合的前病毒没有不寻常的特征，因此对免疫系统是不可见的。因此，在缺乏抗病毒治疗的情况下，有效的免疫逃避使HIV-1能够在数年内维持高水平的复制，直到免疫系统耗尽，感染者发展为AIDS。HIV-1蛋白通常不作为PAMP，尽管病毒衣壳蛋白是否可能被感知以刺激感染细胞中显著的先天免疫激活仍存在争议。3 Wang及其同事现在证明，病毒蛋白酶的过早激活刺激CARD 8炎性小体并诱导HIV-1感染的CD 4 + T细胞的热凋亡。他们的结果确定了一种新的机制，允许先天免疫感应HIV-1，并扩大了先前的数据，表明CARD 8炎性小体激活触发CD 4 + T细胞的细胞凋亡。通常，HIV-1蛋白酶在感染细胞中保持非活性状态，仅通过自动加工从Gag-Pol多蛋白前体中释放出来，需要在成熟病毒体中形成瞬时二聚体。然而，该蛋白酶可被过早激活，例如通过Gag-Pol前体的细胞内过表达或用某些非核苷类逆转录酶抑制剂（NNRTI）处理。Wang等人显示，活性细胞内HIV-1蛋白酶在其N末端切割CARD 8两次，从而促进其自身蛋白水解加工和CARD 8炎性体的组装，促进半胱天冬酶-1的募集和活化。随后，半胱天冬酶-1介导促炎细胞因子白细胞介素1β（IL-1β）和IL-18的蛋白水解裂解、成熟和释放。此外，半胱天冬酶-1导致成孔细胞死亡执行器Gasdermin-D（GSDMD）裂解，进而破坏细胞质膜并诱导程序性但高度炎症性的细胞死亡形式，称为细胞凋亡（图1）。这种新的机制增加了炎症体传感器可能被病原体蛋白质触发的证据。例如，已知NAIP/NLR 4C炎性体可被细菌鞭毛蛋白或细菌3型分泌系统激活。此外，炭疽杆菌致死因子对小鼠NLRP 1b炎性小体的诱导涉及该传感器的蛋白水解激活。CARD 8在CD 4 + T细胞中有效表达，...
A recent study published in Science 1 by Wang and colleagues shows that premature activation of the HIV-1 protease leads to caspase activation and recruitment domain 8 (CARD8) inflammasomemediated pyroptosis of infected macrophages and CD4+ T cells (Fig. 1). These findings might help to improve approaches aiming to eliminate the latent viral reservoirs upon HIV-1 reactivation. Most invading viral pathogens trigger the innate immune system and are usually rapidly controlled and eventually eliminated. Cells sense viral intruders via so-called pattern recognition receptors (PRRs) capable of detecting pathogenassociated molecular patterns (PAMPs) allowing discrimination between self and non-self. In many cases, these patterns are viral nucleic acids that show pathogen-specific structures or emerge at the wrong localization in the cell. Ultimately, activation of PRRs by their respective ligands leads to the induction of various anti-viral signaling cascades, among them the inflammasome. HIV-1, the main causative agent of AIDS, however, is well known for its ability to evade innate immune sensing. For example, accumulating evidence shows that the viral capsid remains largely intact upon viral entry thereby shielding the intermediates of the reverse transcription (RT) process against pattern recognition. 2 The integrated provirus does not have unusual features and is thus invisible to the immune system. Thus, in the absence of antiviral therapy, efficient immune evasion allows HIV-1 to maintain high levels of replication over several years until the immune system is exhausted and infected individuals develop AIDS. HIV-1 proteins do usually not act as PAMPs, although it is under debate whether the viral capsid protein might be sensed to stimulate significant innate immune activation in infected cells. 3 Wang and co-workers now demonstrate that premature activation of the viral protease stimulates the CARD8 inflammasome and induces pyroptosis of HIV-1-infected CD4+ T cells. Their results identify a novel mechanism allowing innate immune sensing of HIV-1 and expand previous data showing that CARD8 inflammasome activation triggers pyroptosis in CD4+ T cells. 4 Usually, the HIV-1 protease is kept in an inactive state in infected cells and is only liberated from the Gag-Pol polyprotein precursor by autoprocessing, requiring transient dimer formation in the maturing virion. However, the protease can be prematurely activated eg by intracellular overexpression of the Gag-Pol precursor or treatment with certain non-nucleosidic reverse transcriptase inhibitors (NNRTIs). Wang et al. show that active intracellular HIV-1 protease cleaves CARD8 twice at its N-terminus, thereby facilitating its autoproteolytic processing and assembly of CARD8 inflammasomes, promoting recruitment and activation of caspase-1. Subsequently, caspase-1 mediates proteolytic cleavage, maturation and release of the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18. In addition, caspase-1 leads to cleavage of the pore-forming cell death executor Gasdermin-D (GSDMD), which in turn ruptures the cytoplasmic membrane and induces a programmed, but highly inflammatory form of cell death called pyroptosis (Fig. 1). This novel mechanism adds to the evidence that inflammasome sensors may be triggered by proteins of pathogens. For example, it is known that the NAIP/NLR4C inflammasome can be activated by bacterial flagellins or the bacterial type-3 secretion system. In addition, induction of the mouse NLRP1b inflammasome by the Bacillus anthracis lethal factor involves proteolytic activation of this sensor. CARD8 is efficiently expressed in CD4+ T cells and …
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.5
作者：
Zila V;Margiotta E;Turoňová B;Müller TG;Zimmerli CE;Mattei S;Allegretti M;Börner K;Rada J;Müller B;Lusic M;Kräusslich HG;Beck M
通讯作者：
Beck M
DOI：
10.1126/science.abe1707
发表时间：
2021-03-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wang Q;Gao H;Clark KM;Mugisha CS;Davis K;Tang JP;Harlan GH;DeSelm CJ;Presti RM;Kutluay SB;Shan L
通讯作者：
Shan L
DOI：
10.15252/embj.2020105071
发表时间：
2020-10-01
期刊：
The EMBO journal
影响因子：
--
作者：
Linder A;Bauernfried S;Cheng Y;Albanese M;Jung C;Keppler OT;Hornung V
通讯作者：
Hornung V