Virus Transmission

摘要 艾滋病毒/艾滋病流行病仍然是人类健康的全球负担。 减少艾滋病毒感染的死亡，预防性疫苗和数百万感染者的功能性治疗， 2要在这些领域取得成功，就需要更好地了解艾滋病毒的传播和扩散 以及CD 4 T细胞耗竭的机制，这是免疫缺陷的标志。3此外， 开发针对HIV包膜（Env）的抗病毒疗法和疫苗，Env是HIV表面上唯一的病毒蛋白， HIV病毒体4，5需要了解其构象动力学以及它如何被病毒宿主细胞激活 核聚变我们建议通过成像实验来填补这些知识空白，这些实验将：1）可视化 HIV-1在人源化小鼠模型和非人灵长类动物中传播后的传播6 -9，2） 确定CD 4耗竭的原因并可视化病毒限制的细胞事件，3）描绘 HIV Env三聚体如何被激活以进行融合10，11和4）定义Env如何被宿主细胞限制性抑制 12 -14这种方法将揭示病毒传播的瓶颈， 限制，和弱点，在激活艾滋病毒包膜，可以利用治疗。

ABSTRACT The HIV/AIDS pandemic remains a global burden on human health.1 Although antiretroviral therapy (ART) reduces deaths from HIV infection, prophylactic vaccine(s) and a functional cure for the millions infected are lacking.2 Success in these areas will require improved understanding of HIV transmission and dissemination and the mechanism of CD4 T cell depletion, which is the hallmark of immune deficiency.3 In addition, developing antiviral therapies and vaccines against HIV envelope (Env), the only viral protein on the surface of the HIV virion4,5, requires understanding its conformational dynamics and how it is activated for virus–host cell fusion. We propose to fill these knowledge gaps through imaging experiments that will: 1) Visualize the dissemination of HIV-1 following transmission in humanized mouse models and non-human primates6-9, 2) Determine the cause of CD4 depletion and visualize cellular events underlying viral restriction, 3) Delineate how the HIV Env trimer is activated for fusion10,11, and 4) Define how Env is inhibited by host cell restriction proteins of the SERINC family.12-14 This approach will reveal bottlenecks in virus dissemination, mechanisms of restriction, and vulnerabilities in activating HIV Env that can be exploited therapeutically.