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推动了艾滋病的进展。有趣的是，HIV-1感染的这些特征在非人类灵长类动物中缺失，这些灵长类动物自然感染SIV，即使病毒载量很高也不会发病。HIV-1和SIV感染的这些不同临床结果的原因仍然知之甚少。我们推测，HIV-1的一些特征，如VPU基因的存在，Nef下调TCR-CD3的缺乏，以及共同受体CXCR4的频繁使用，可能会使这种病毒特别毒力。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(干扰素)，并且功能正常的VPU基因有助于这一效果。此外，我们发现Nef介导的TCR-CD3的下调特异性地保护了CD4+记忆T细胞免受程序性死亡。在这里，我们想要进一步定义这些影响。I型干扰素主要由CD4介导的血浆细胞样树突状细胞(PDCs)摄取病毒粒子并随后触发Toll样受体(TLRs)诱导。因此，HIV-1可能诱导特别高水平的I型干扰素，因为VPU介导的Tetherin和CD4降解的拮抗作用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”SIV克隆的比较分析，我们将确定HIV-1的特异性特征与炎性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自然灵长类宿主以良性关系共存，因为它们的Nef蛋白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，目前还不清楚人体内的哪些循环因素调节了艾滋病毒引起的炎症和细胞凋亡。因此，我们将筛选血液来源的多肽-蛋白质文库，以确定调节这些过程的循环因素。我们的长期愿景是进一步优化这些炎症反应和HIV依赖的细胞凋亡的自然调节因子，以防止已治疗和未治疗的HIV感染者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.