The role of bystander cell autophagy in HIV-1 infection

人类免疫缺陷病毒1（HIV-1）的有效传播受到未感染的旁观者细胞的可用性和抗病毒状态的控制。抗病毒状态由先天性和内在免疫抗病毒效应子途径（例如自噬）的活性定义。自噬是一种以细胞蛋白或病毒成分为目标进行破坏的自动消化过程。与其他免疫途径一样，自噬在感染HIV-1后被诱导。然而，对反应的解剖揭示了HIV-1感染的CD 4 + T细胞中的自噬水平令人惊讶地低。相反，在未感染的旁观者T细胞中，诱导高水平的自噬。我们的数据进一步表明，旁观者自噬是由HIV-1感染的T细胞释放的可溶性因子诱导的。我们打算在分子水平上确定HIV-1感染中旁观者细胞自噬诱导是如何起作用的。为此，我们将确定感染细胞中诱导未知自噬诱导因子释放的细胞传感途径和病毒决定簇。此外，我们将确定信号传导因子在哪些细胞类型上诱导自噬以及哪些细胞类型在感染后释放它。最后，我们将使用先进的CRISPR方法来定义旁观者细胞中自噬上调的决定因素。为了了解旁观者自噬的影响，我们将确定其对HIV 1感染T细胞的后果。我们的初步数据表明，具有高自噬通量的细胞对HIV-1的容忍度较低，因此病毒传播受到限制。然而，自噬的激活最终可能会付出代价。由过度自噬诱导的细胞死亡可能导致旁观者T细胞的耗竭，这是AIDS的标志。总之，该项目将产生新的见解艾滋病的发病机制，艾滋病毒-1与自噬的相互作用，并探索细胞内在防御的调控特征。我们的目的是建立旁分泌自噬激活的新概念，并确定相关的关键因素。了解HIV-1感染期间旁观者细胞自噬的影响和调节将使我们能够设计策略来微调抗病毒细胞内在免疫。由于自噬是一种广泛活性的抗微生物途径，这些策略可能是未来不仅针对HIV-1而且针对其他病原体的治疗或预防方法的基础。此外，这些对自噬的基本见解可能与自噬失调的疾病有关，其中包括癌症和神经病理学。该项目将通过引入自噬而受益于SPP并补充SPP，同时牢牢扎根于HIV-1的感知和限制。我相信，这一提案的概念将为其他项目带来新的动力，从而在SPP内部培育新的合作。

Efficient spread of human immunodeficiency virus 1 (HIV-1) is controlled by the availability and anti-viral state of non-infected bystander cells. The anti-viral state is defined by the activity of innate and intrinsic immune antiviral effector pathways, such as autophagy. Autophagy is an auto-digestive process targeting cellular proteins or viral components for destruction. Like other immune pathways, autophagy is induced upon infection with HIV-1. However, dissection of the response revealed that autophagy levels in HIV-1 infected CD4+ T cells are surprisingly low. In contrast, in non-infected bystander T cells high levels of autophagy are induced. Our data further showed that bystander autophagy is induced by a soluble factor released from HIV-1 infected T cells. We intend to determine how bystander cell autophagy induction in HIV-1 infection works on a molecular level. To this end, we will determine cellular sensing pathways and viral determinants in infected cells that induce the release of the unknown autophagy-inducing factor. Furthermore, we will determine the identity of the signalling factor on which cell types it induces autophagy and which cell types release it after infection. Finally, we will use advanced CRISPR approaches to define determinants of autophagy upregulation in bystander cells. To understand the impact of bystander autophagy, we will determine its consequences on HIV 1 infection of T cells. Our preliminary data show that cells with high autophagic flux are less permissive for HIV-1, thus viral spread is limited. However, activation of autophagy may eventually come at a cost. Cell death induced by excessive autophagy may contribute to depletion of bystander T cells, a hallmark of AIDS. Taken together, this project will yield novel insights into the pathogenesis of AIDS, interplay of HIV-1 with autophagy and explore regulatory features of cell intrinsic defenses. We aim to establish the novel concept of paracrine autophagy activation and define key factors involved. Understanding the impact and regulation of bystander cell autophagy during HIV-1 infection will allow us to design strategies to fine-tune anti-viral cell-intrinsic immunity. Since autophagy is a broadly active anti-microbial pathway these strategies may be the basis of future therapeutic or preventive approaches targeting not only HIV-1 but also other pathogens. Furthermore, these fundamental insights into autophagy may be relevant for diseases where autophagy is dysregulated, among them cancer and neuropathologies.This project will benefit from and complement the SPP by introducing autophagy, while being firmly rooted in sensing and restriction of HIV-1. I believe that concepts of this proposal will spark new impulses for other projects and thus nurture new collaborations within the SPP.