The Vif-APOBEC Nexus

A3介导的限制性酶切的定义标志，解释了基因组正链G到A的突变， 患者来源的病毒序列。然而，该病毒部署了一个反击战略，利用病毒 编码的“病毒体感染因子”（Vif）通过细胞内的 E3-泛素连接酶复合物。在这里，我将使用稳健和无偏的实验方法来1）识别 对A3 D和A3 F限制显示不同活性的功能分离Vif突变体 酶和2）定义调节A3的抗HIV-1活性的细胞机制。我的研究会 利用假设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。我希望有一个更好的 了解Vif/A3表面和管理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， 促进NIAID的总体优先事项“支持治疗或治愈艾滋病毒的创新战略 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.”