(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.

项目摘要 伽马梅氏病毒感染与包括B细胞在内的许多恶性肿瘤有关 淋巴增生性疾病，胃癌，鼻咽癌。这样的免疫缺陷个体 随着HIV患者更容易受到γ-疱疹病毒相关的癌症的影响。通常需要几个月 癌症在原发性感染后出现了几年。这个观察突出了多步 癌变的过程只能通过病毒持续感染来实现。 EBV和KSHV为γ- 疱疹病毒在淋巴样细胞中建立潜在感染，并在宿主的余生中维持。 这些病毒储层的间歇性重新激活将导致更多的病毒生产和扩散。虽然 有一些抗病毒药物专门针对γ-疱疹病毒的裂解复制，它们不会消除这些药物 潜在病毒可以作为病毒相关癌症的危险因素。 我们的小组最近表明，HIV感染导致polo样激酶1（PLK1）的激活，一种原始的。 癌基因，在B和T细胞淋巴细胞中。 PLK1是控制G2-M细胞周期的丝氨酸/苏氨酸激酶 进展，经常在广泛的癌症中过表达。它的抑制剂已被开发为 有希望的癌症治疗。我们进一步发现，PLK1都参与了EBV/kshv延迟的调节 其细胞储量的存活在宿主中。蛋白质敲低以及PLK1的化学抑制 能够重新激活潜在的EBV/kSHV并促进γ-肝病毒反应B淋巴细胞的细胞死亡。 这些结果暴露了一种新的病毒机制，该机制可以描述如何共同感染γ-HERPESVIRUSS呈现 艾滋病毒患者对癌症的风险增加了，浮它是HIV本身不是致癌的事实。我们的调查 将三个单独的目的包括：（1）分子研究 HIV1在EBV/KSHV感染的淋巴细胞中激活PLK1的机理。 （2）调查PLK1的调查 调节EBV/KSHV延迟和其细胞储层的维护。 （3）抑制PLK1作为新颖的 通过消除其细胞储量，用于放射性EBV/KSHV持续感染。 总的来说，我们拟议的研究将有助于理解艾滋病毒的潜伏期和 γ掌病毒感染是各种病毒相关癌症的基础。这个项目也将有助于 确定治愈HIV和EBV/KSHV感染及其相关恶性肿瘤的新分子靶标。