The Vif-APOBEC Nexus

A3介导的限制的定义特征，解释了基因组+链G-to-A突变 患者派生的病毒序列。然而，该病毒部署了一种利用该病毒的对抗策略 编码的“病毒粒子感染性因子”(VIF)可通过细胞因子泛素化和降解A3s。 E3-泛素连接酶复合体。在这里，我将使用稳健和公正的实验方法来识别 针对A3D和A3F限制显示不同活性的功能分离Vif突变体 酶和2)确定调节A3s抗HIV-1活性的细胞机制。我的学习将会 利用假说和技术驱动的方法以及基础病毒学的组合， 遗传学/基因组工程、细胞生物学和生物化学技术。我期待着一个更好的 了解Vif/A3表面和控制A3抗病毒的潜在细胞机制 活性有可能导致新的策略，以提高这些酶的抗HIV-1活性和 为NIAID的总体优先事项“支持治疗或治愈艾滋病毒的创新战略”作出贡献 感染。“

The defining hallmark of A3-mediated restriction, explaining genomic plus strand G-to-A mutations in patient-derived viral sequences. However, the virus deploys a counteraction strategy that utilizes the virus encoded “virion infectivity factor” (Vif) to polyubiquitinate and degrade the A3s through a cellular E3-ubiquitin ligase complex. Here, I will use robust and unbiased experimental approaches to 1) identify separation-of-function Vif mutants that display differential activity against A3D and A3F restriction enzymes and 2) define the cellular mechanisms that regulate anti-HIV-1 activity of the A3s. My studies will utilize both hypothesis- and technology-driven approaches and a combination of fundamental virology, genetics/genome engineering, cell biology, and biochemistry techniques. I anticipate that a better understanding of the Vif/A3 surfaces and the underlying cellular mechanisms that govern A3 antiviral activity has the potential to lead to novel strategies to boost the anti-HIV-1 activities of these enzymes and contribute to the overall NIAID priority of “supporting innovative strategies for treating or curing HIV infection.”