Unraveling the molecular link between HIVAIDS and cancer

我们公正的蛋白质组质谱和随后的生化分析显示 Plk 4与细胞支架蛋白的C-末端酸性结构域（1401-1507）结合， VprBP，通过其C-末端神秘的Polo盒。引人注目的是，HIV-1 Vpr与WD 40结合， 结构域（1003-1400）的VprBP，大大增强了VprBP-Plk 4的相互作用，并诱导VprBP-Plk 4的表达。 Vpr-VprBP-Plk 4复合物的形成。所有三种蛋白质共定位于中心体， 三元复合物的形成似乎增强Plk 4介导的中心粒复制。 与这些发现相一致，VprBP通过稳定Plk 4的表达来促进Plk 4的功能。 中心粒结合状态，而不是诱导其蛋白酶体降解，如观察到的 用于Vpx-VprBP-SAMHD 1复合物和其他细胞靶点。这些数据表明，当 当细胞感染HIV-1时，Vpr可能通过形成Vpr-VprBP-Plk 4改变Plk 4的功能， 复合物在生理条件下诱导Plk 4依赖的中心粒过度复制， 导致非整倍体和癌症的细胞事件。一种结构上相关的HIV-2 Vpx未能 与VprBP和Plk 4相互作用，表明HIV-1 Vpr诱导事件的特异性。基于 根据这些观察，我们假设HIV-1 Vpr可以直接改变基因组的稳定性， 通过劫持细胞Plk 4-VprBP复合物促进癌发生。更多的研究 计划在生理条件下确定三元Vpr-VprBP-Plk 4复合物的作用， 在动物模型中使用HIV-1易感细胞和组织。本研究 可以揭示可能直接将艾滋病毒/艾滋病与其病因联系起来的机制， 共病癌症此外，它可能提供一个新的范式，在理解增加的 HIV-1感染者的癌症风险。调查艾滋病毒引起的合并症是其中一个 四个指定的NIH HIV/AIDS研究优先事项。这项研究旨在直接 解决HIV-1相关的癌症合并症。我们取得了丰富的经验， 研究HIV蛋白质如何与细胞靶点相互作用， 各种生化和结构分析。此外，我们努力确定 Vpr-VprBP-Plk 4复合物的四级结构一直在沿着很好地移动。一旦 四级结构确定后，我们将有兴趣设计抑制剂， 破坏复合物，从而有助于防止HIV-1诱导的中心体异常及其 相关的人类疾病，如癌症。

Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein, VprBP, via its C-terminal cryptic polo-box. Strikingly, HIV-1 Vpr, which binds to the WD40 domain (1003-1400) of VprBP, greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the formation of the ternary complex appeared to augment Plk4-mediated centriole duplication. Consistent with these findings, VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation, as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that, when cells are infected with HIV-1, Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication, a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4, indicating the specificity of HIV-1 Vpr-induced events. Based on these observations, we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions, using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore, it may offer a new paradigm in understanding the increased cancer risk in people living with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Furthermore, our efforts to determine the quaternary structure of the Vpr-VprBP-Plk4 complex have been moving along well. Once the quaternary structure is determined, we will be interested in designing inhibitors that could disrupt the complex and thus help prevent HIV-1-induced centrosomal abnormalities and their associated human disorders, such as cancer.