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

异常的免疫激活和增加的细胞凋亡驱动进展到艾滋病。有趣的是，HIV-1感染的这些特征在自然感染SIV的非人灵长类动物中是不存在的，尽管病毒载量很高，但这些灵长类动物并不发病。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，Nef对TCR-CD 3的下调缺乏，以及辅助受体CXCR 4的频繁使用可能使该病毒特别致命。我们的初步数据支持，HIV-1诱导更高水平的I型干扰素（IFN）比HIV-2或SIV和功能vpu基因有助于这种效果。此外，我们发现Nef介导的TCR-CD 3下调特异性保护CD 4+记忆T细胞免于程序性死亡。在这里，我们想进一步定义这些影响。I型IFN主要由浆细胞样树突状细胞（pDC）的CD 4介导的病毒体摄取和随后的Toll样受体（TLR）的触发诱导。因此，HIV-1可以诱导特别高水平的I型IFN，因为Vpu介导的对系链蛋白和CD 4降解的拮抗作用增加了病毒体释放和HIV-1与CD 4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以与它们的天然灵长类宿主良性共存，因为它们的Nef蛋白可以保护对免疫功能至关重要的T细胞亚群免受程序性死亡。最后，目前对人体中哪些循环因子调节HIV诱导的炎症和细胞凋亡知之甚少。因此，我们将筛选血液来源的肽蛋白库，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的HIV感染个体的破坏性慢性免疫激活。

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.