Virus Transmission

摘要 艾滋病毒/艾滋病大流行仍然是人类健康的全球负担1，尽管抗逆转录病毒疗法(抗逆转录病毒疗法) 减少艾滋病毒感染的死亡，预防性疫苗(S)和数百万感染者的功能性治疗是 在这些领域取得成功需要更好地了解艾滋病毒的传播和传播 以及CD4T细胞耗尽的机制，这是免疫缺陷的标志。 正在开发针对HIV包膜(Env)的抗病毒疗法和疫苗，Env是病毒表面唯一的病毒蛋白 HIV病毒4，5需要了解它的构象动力学以及它是如何被病毒宿主细胞激活的 核聚变。我们建议通过成像实验填补这些知识空白，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6-9，2) 确定CD4耗尽的原因并可视化病毒限制背后的细胞事件，3)描述 HIV Env三聚体如何被激活以进行融合10、11和4)确定Env如何被宿主细胞限制所抑制 12-14这种方法将揭示病毒传播的瓶颈，机制 限制，以及在激活艾滋病毒环境中可用于治疗的漏洞。

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.