The role of bystander cell autophagy in HIV-1 infection

人类免疫缺陷病毒1 （HIV-1）的有效传播是由未感染的旁观者细胞的可用性和抗病毒状态控制的。抗病毒状态是由先天免疫和内在免疫抗病毒效应途径（如自噬）的活性定义的。自噬是一种针对细胞蛋白或病毒成分进行破坏的自我消化过程。像其他免疫途径一样，自噬在HIV-1感染后被诱导。然而，对反应的解剖显示，HIV-1感染的CD4+ T细胞的自噬水平出奇地低。相反，在未感染的旁观者T细胞诱导高水平的自噬。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。我们打算确定旁观者细胞自噬诱导HIV-1感染如何在分子水平上起作用。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感应途径和病毒决定因素。此外，我们将确定信号因子在哪些细胞类型上诱导自噬，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的容容度较低，因此病毒的传播受到限制。然而，自噬的激活最终可能是有代价的。过度自噬诱导的细胞死亡可能导致旁观者T细胞的耗竭，这是艾滋病的一个标志。综上所述，该项目将对艾滋病的发病机制、HIV-1与自噬的相互作用以及细胞内在防御的调控特性产生新的见解。我们旨在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固有免疫。由于自噬是一种广泛活跃的抗微生物途径，这些策略可能是未来针对HIV-1和其他病原体的治疗或预防方法的基础。此外，这些关于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。该项目将受益于SPP，并通过引入自噬来补充SPP，同时牢牢扎根于对HIV-1的感知和限制。我相信，这一建议的概念将为其他项目激发新的动力，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.