Type I interferon induction and elimination of memory T cells by HIV and other primate lentiviruses

HIV 和其他灵长类慢病毒对 I 型干扰素的诱导和消除记忆 T 细胞

• 批准号: 236600002
• 负责人: Professor Dr. Frank Kirchhoff
• 金额: --
• 依托单位: School of Medicine
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236600002?language=en
• 关键词: Type; interferon; induction; elimination; memory

Aberrant immune activation and increased apoptosis drive progression to AIDS. Interestingly, these characteristic features of HIV-1 infection are absent in non-human primates that are naturally infected with SIV and do not develop disease despite high viral loads. The reasons for these different clinical outcomes of HIV-1 and SIV infection remain poorly understood. We hypothesize that some features that are characteristic of HIV-1, such as the presence of a vpu gene, the lack of TCR-CD3 down-modulation by Nef, and frequent usage of the coreceptor CXCR4 may render this virus particularly virulent. Our preliminary data support that HIV-1 induces higher levels of type I interferons (IFN) than HIV-2 or SIV and that a functional vpu gene contributes to this effect. Furthermore, we found that Nef-mediated down-modulation of TCR-CD3 specifically protects CD4+ memory T cells against programmed death. Here, we want to further define these effects. Type I IFN is mainly induced by CD4-mediated virion uptake by plasmacytoid dendritic cells (pDCs) and subsequent triggering of Toll-like receptors (TLRs). Thus, HIV-1 may induce particularly high levels of type I IFN because Vpu-mediated antagonism of tetherin and CD4 degradation increases virion release and binding of HIV-1 to CD4. Through comparative analyzes of HIV-1 with "non-pathogenic" SIV clones, we will determine the relevance of HIV-1-specific features for inflammatory cytokine induction. Furthermore, we will determine whether most primate lentiviruses may coexist in a benign relationship with their natural primate hosts because their Nef proteins protect T cell subsets that are critical for immune function against programmed death. Finally, it is currently poorly understood which circulating factors in the human body modulate HIV-induced inflammation and apoptosis. Thus, we will screen blood-derived peptide-protein libraries to identify circulating factors modulating these processes. Our long-term vision is to further optimize such natural modulators of inflammatory responses and HIV-dependent apoptosis to prevent the damaging chronic immune activation in treated and untreated HIV-infected individuals.

异常的免疫激活和增加的细胞凋亡驱动艾滋病的进展。有趣的是，这些HIV-1感染的特征在自然感染SIV的非人类灵长类动物中不存在，尽管病毒载量很高，但它们不会发病。HIV-1和SIV感染的这些不同临床结果的原因仍然知之甚少。我们假设HIV-1的一些特征，如vpu基因的存在，缺乏Nef对TCR-CD3的下调，以及频繁使用辅助受体CXCR4，可能使这种病毒具有特别的毒性。我们的初步数据支持HIV-1比HIV-2或SIV诱导更高水平的I型干扰素（IFN），并且功能性vpu基因有助于这种效果。此外，我们发现nef介导的TCR-CD3下调特异性地保护CD4+记忆T细胞免受程序性死亡。在这里，我们想进一步定义这些效果。I型IFN主要由浆细胞样树突状细胞（pDCs）摄取cd4介导的病毒粒子和随后触发toll样受体（TLRs）诱导。因此，HIV-1可能诱导特别高水平的I型IFN，因为vpu介导的tetherin和CD4降解的拮抗增加了病毒粒子的释放和HIV-1与CD4的结合。通过对HIV-1与“非致病性”SIV克隆的比较分析，我们将确定HIV-1特异性特征与炎症细胞因子诱导的相关性。此外，我们将确定大多数灵长类慢病毒是否可能与它们的天然灵长类宿主以良性关系共存，因为它们的Nef蛋白保护T细胞亚群，而T细胞亚群对免疫功能抵抗程序性死亡至关重要。最后，目前还不清楚人体中哪些循环因子调节hiv诱导的炎症和细胞凋亡。因此，我们将筛选血液来源的肽蛋白文库，以确定调节这些过程的循环因子。我们的长期愿景是进一步优化这种炎症反应和hiv依赖性细胞凋亡的天然调节剂，以防止治疗和未治疗hiv感染者的破坏性慢性免疫激活。

项目成果

HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4+ T Cells.

• DOI: 10.1016/j.celrep.2016.09.023
• 发表时间: 2016-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: J. Vermeíre;F. Roesch;D. Sauter;Rejane Rua;Dominik Hotter;A. V. Van Nuffel;H. Vanderstraeten;E. Naessens;Veronica Iannucci;Alessia Landi;Wojciech Witkowski;Ann Baeyens;F. Kirchhoff;B. Verhasselt

Limited HIV infection of central memory and stem cell memory CD4+ T cells is associated with lack of progression in viremic individuals.

• DOI: 10.1371/journal.ppat.1004345
• 发表时间: 2014-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Klatt NR;Bosinger SE;Peck M;Richert-Spuhler LE;Heigele A;Gile JP;Patel N;Taaffe J;Julg B;Camerini D;Torti C;Martin JN;Deeks SG;Sinclair E;Hecht FM;Lederman MM;Paiardini M;Kirchhoff F;Brenchley JM;Hunt PW;Silvestri G
• 通讯作者: Silvestri G