(PQ4) Role of HIV-induced PLK1 Activation in Regulation of gamma-Herpesvirus Reservoirs in Lymphocytes

(PQ4) HIV 诱导的 PLK1 激活在调节淋巴细胞中 γ-疱疹病毒储库中的作用

• 批准号: 10228415
• 负责人: Netty G Santoso
• 金额: $ 38.81万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-11 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10228415
• 关键词: AIDS-Related Lymphoma; Acquired Immunodeficiency Syndrome; Address; Affect; Antiviral Agents; Apoptosis; Attenuated; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Burkitt Lymphoma; CD4 Positive T Lymphocytes; Cancer Etiology; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Tropism; Cessation of life; Chemicals; Chromatin; Clinical Trials; DNA Damage; Development; Dissection; Double Stranded DNA Virus; Drug Combinations; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Lymphoma; Etiology; HIV; HIV Infections; HIV Seropositivity; HIV-1; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune signaling; Immunocompromised Host; Individual; Infection; Infectious Agent; Investigation; Kaposi Sarcoma; Knowledge; Lead; Life; Link; Lymphocyte; Lymphoid Cell; Lymphoma; Lymphoproliferative Disorders; M cell; Maintenance; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; Molecular; Molecular Target; Nasopharynx Carcinoma; Non-Hodgkin' s Lymphoma; Nuclear; Oncogenic; Oncolytic; Organ Transplantation; Oxidative Stress; PLK1 gene; Patients; Phosphotransferases; Play; Post-Translational Protein Processing; Primary Infection; Process; Production; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogenes; Regimen; Regulation; Reporting; Research; Rest; Risk; Risk Factors; Role; Shock; Signal Transduction; Soft Tissue Neoplasms; Specific qualifier value; Stomach Carcinoma; Stress; Sumoylation Pathway; T-Lymphocyte; TP53 gene; Therapeutic; Viral; Viral Proteins; Viral reservoir; Virus; Virus Diseases; Virus Latency; base; biological adaptation to stress; cancer therapy; carcinogenesis; chronic infection; co-infection; effective therapy; feasibility testing; gammaherpesvirus; infected B cell; inhibitor/antagonist; kinase inhibitor; knock-down; large cell Diffuse non-Hodgkin' s lymphoma; latent infection; lytic replication; nef Protein; neoplastic cell; novel; novel therapeutic intervention; overexpression; pathogen; polo-like kinase kinase 1; prevent; primary effusion lymphoma; response; targeted cancer therapy; tumorigenesis; virus related cancer

PROJECT SUMMARY Gammaherpesvirus infections are associated with a number of malignancies that include B-cell lymphoproliferative diseases, gastric carcinoma, nasopharyngeal carcinoma. Immunodeficient individuals such as HIV patients are more susceptible to γ -herpesviruses-associated cancers. It generally takes several months to years for cancer to arise after primary infection with the virus. This observation highlights the multistep process of carcinogenesis that could only be achieved by viral persistent infection. EBV and KSHV are γ - herpesviruses that establish latent infection in lymphoid cell, which is maintained for the rest of the host’s life. Intermittent reactivation of these viral reservoirs will lead to more viruses production and spreading. Although there are antiviral drugs that specifically target lytic replication of γ -herpesviruses, they do not eliminate those latent viruses that could serve as a risk factor for viral-associated cancers. Our group recently showed that HIV infection leads to activation of Polo-like kinase 1 (PLK1), a proto- oncogene, in B and T-cell lymphocytes. PLK1 is a serine/threonine kinase that controls G2-M cell cycle progression and is frequently overexpressed in wide range of cancers. Its inhibitors have been developed as promising cancer therapy. We further discovered that PLK1 is involved in both regulation of EBV/KSHV latency and survival of their cellular reservoirs in the host. Protein knockdown as well as chemical inhibition of PLK1 was able to reactivate latent EBV/KSHV and promote cell death of γ -herpesvirus-reactivated B lymphocytes. These results expose a new viral mechanism that can describe how co-infection of γ -herpesviruses renders HIV patients an increased risk to cancers, despite the fact that HIV itself is not oncogenic. Our investigations into this topic will be accomplished by three separate aims that include: (1) Investigation of molecular mechanism of PLK1 activation by HIV1 in EBV/KSHV-infected lymphocytes. (2) Investigation of how PLK1 regulates EBV/KSHV latency and maintenance of their cellular reservoirs. (3) Inhibition of PLK1 as novel means to eradicate EBV/KSHV persistent infection by eliminating their cellular reservoirs. Collectively, our proposed studies will contribute to the understanding of latency in HIV and gammaherpesviruses infections that underlie various viral-associated cancers. This project will also help to identify new molecular target for curing HIV and EBV/KSHV infections and their-related malignancies.

项目概要 伽马疱疹病毒感染与许多恶性肿瘤相关，其中包括 B 细胞恶性肿瘤 淋巴组织增生性疾病、胃癌、鼻咽癌等免疫缺陷个体。 由于艾滋病毒患者更容易患γ-疱疹病毒相关癌症，因此通常需要几个月的时间。 初次感染病毒后癌症的发生需要数年时间，这一观察结果强调了多步骤的过程。 只有通过病毒持续感染才能实现的致癌过程是γ-。 疱疹病毒在淋巴细胞中建立潜伏感染，并在宿主的余生中维持这种感染。 这些病毒库的间歇性重新激活将导致更多病毒的产生和传播。 有一些抗病毒药物专门针对 γ 疱疹病毒的裂解性复制，但它们并不能消除这些病毒 潜伏病毒可能成为病毒相关癌症的危险因素。 我们的小组最近表明，HIV 感染会导致 Polo 样激酶 1 (PLK1) 的激活，PLK1 是一种原 B 细胞和 T 细胞淋巴细胞中的癌基因 PLK1 是一种控制 G2-M 细胞周期的丝氨酸/苏氨酸激酶。 其抑制剂已被开发为多种癌症。 我们进一步发现 PLK1 参与 EBV/KSHV 潜伏期的调节。 以及它们的细胞储存库在宿主中的存活以及蛋白质敲除以及 PLK1 的化学抑制。 能够重新激活潜伏的 EBV/KSHV 并促进γ-疱疹病毒重新激活的 B 淋巴细胞的细胞死亡。 这些结果揭示了一种新的病毒机制，可以描述γ-疱疹病毒的共同感染如何导致 尽管艾滋病毒本身并不致癌，但艾滋病毒患者患癌症的风险增加。 该主题将通过三个不同的目标来完成，其中包括：（1）分子生物学的研究 HIV1在EBV/KSHV感染的淋巴细胞中激活PLK1的机制（2）PLK1如何激活的研究。 调节 EBV/KSHV 潜伏期及其细胞储存库的维持 (3) 抑制 PLK1 作为新型药物。 指通过消除细胞储存库来根除 EBV/KSHV 持续感染。 总的来说，我们提出的研究将有助于了解艾滋病毒的潜伏期和 该项目也将有助于研究导致各种病毒相关癌症的伽玛疱疹病毒感染。 确定治疗 HIV 和 EBV/KSHV 感染及其相关恶性肿瘤的新分子靶标。