Unraveling the molecular link between HIVAIDS and cancer

揭示艾滋病毒和癌症之间的分子联系

• 批准号: 10926459
• 负责人: Kyung Lee
• 金额: $ 51.83万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926459
• 关键词: Acidic Region; Acquired Immunodeficiency Syndrome; Address; Aneuploidy; Animal Model; Binding; Biochemical; Biological; Biological Assay; Blood; C-terminal; CD4 Positive T Lymphocytes; Cell Cycle; Cell model; Cell physiology; Cells; Centrioles; Centrosome; Complex; Cryoelectron Microscopy; Cultured Cells; Data; Development; Disease; Etiology; Event; Genome Stability; Goals; HIV; HIV-1; HIV-2; HIV/AIDS; Human; Immune system; Incidence; Infection; Investigation; Light; Link; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Nature; Organelles; PLK1 gene; Pathogenesis; Persons; Phosphotransferases; Physiological; Predisposition; Process; Proteins; Proteomics; Research; Research Priority; Risk; Role; Scaffolding Protein; Shapes; Specificity; Structure; T-Lymphocyte; Tail; Tissues; United States National Institutes of Health; WD Repeat; Work; X-Ray Crystallography; antiretroviral therapy; cancer risk; carcinogenesis; cellular targeting; chromosome missegregation; comorbidity; design; experience; high risk; inhibitor; interest; novel strategies; prevent; scaffold; tumorigenesis

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 ternary complex formation 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 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. The data that we obtained from various cultured cells revealed that disrupting the Vpr-VprBP-Plk4 complex by either deleting the Vpr's C-terminal tail or the VprBP's acidic region was sufficient to abolish Vpr-dependent centrosome amplification and aneuploidy in multiple CD4+ cells, including primary T cells. Given the tight association of aneuploidy and cancer, these findings suggest that the HIV-1-induced Vpr-VprBP-Plk4 complex can directly promote oncogenesis in HIV-1-susceptible T cells or other blood Vpr-transducible cells by hijacking the host machinery for Plk4-mediated centriole duplication. In light of the finding that the risk of developing NHL remains high even during the combination antiretroviral therapy, this work may offer a new direction for investigating underlying mechanisms that give rise to HIV-1-associated cancers.

我们的无偏蛋白质组质谱分析和随后的生化分析表明，Plk4 通过其 C 端隐性 polo-box 与细胞支架蛋白 VprBP 的 C 端酸性结构域 (1401-1507) 结合。引人注目的是，HIV-1 Vpr 与 VprBP 的 WD40 结构域 (1003-1400) 结合，大大增强了 VprBP-Plk4 相互作用，并诱导 Vpr-VprBP-Plk4 复合物的形成。所有三种蛋白质共定位于中心体，并且三元复合物的形成似乎增强了 Plk4 介导的中心粒复制。与这些发现一致的是，VprBP 通过稳定其中心粒相关状态而不是诱导其蛋白酶体降解来促进 Plk4 功能，正如在 Vpx-VprBP-SAMHD1 复合物和其他细胞靶标中观察到的那样。这些数据表明，当细胞感染 HIV-1 时，Vpr 可能通过在生理条件下形成 Vpr-VprBP-Plk4 复合物来改变 Plk4 的功能，并诱导 Plk4 依赖性中心粒过度复制，这是一种导致非整倍体和癌症的细胞事件。结构相关的 HIV-2 Vpx 未能与 VprBP 和 Plk4 相互作用，表明 HIV-1 Vpr 诱导事件的特异性。基于这些观察，我们假设 HIV-1 Vpr 可以直接改变基因组稳定性并通过劫持细胞 Plk4-VprBP 复合物促进癌变。计划进行更多研究，以在动物模型中使用 HIV-1 易感细胞和组织来确定三元 Vpr-VprBP-Plk4 复合物在生理相关条件下的作用。这项研究可以揭示艾滋病毒/艾滋病与其合并癌症的病因学直接联系的机制。此外，它可能为理解 HIV-1 感染者癌症风险增加提供一个新的范例。调查艾滋病毒引起的合并症是美国国立卫生研究院指定的四个艾滋病毒/艾滋病研究重点之一。这项研究旨在直接解决与 HIV-1 相关的癌症合并症。我们在研究 HIV 蛋白如何与细胞靶点相互作用以及使用各种生化和基于结构的分析改变细胞生理学方面获得了丰富的经验。此外，我们确定 Vpr-VprBP-Plk4 复合物四级结构的努力进展顺利。一旦确定了四级结构，我们将有兴趣设计能够破坏该复合物的抑制剂，从而有助于预防 HIV-1 诱导的中心体异常及其相关的人类疾病，例如癌症。我们从各种培养细胞中获得的数据表明，通过删除 Vpr 的 C 末端尾部或 VprBP 的酸性区域来破坏 Vpr-VprBP-Plk4 复合物足以消除多种 CD4+ 细胞（包括原代 T 细胞）中的 Vpr 依赖性中心体扩增和非整倍性。鉴于非整倍性与癌症的紧密关联，这些发现表明，HIV-1诱导的Vpr-VprBP-Plk4复合物可以通过劫持宿主机制进行Plk4介导的中心粒复制，直接促进HIV-1易感T细胞或其他血液Vpr转导细胞的肿瘤发生。鉴于即使在联合抗逆转录病毒治疗期间，发生 NHL 的风险仍然很高，这项工作可能为研究引起 HIV-1 相关癌症的潜在机制提供新方向。