权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

(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

基本信息

批准号：
10615879
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
项目类别：
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/10615879
关键词：
AIDS-Related Lymphoma Acquired Immunodeficiency Syndrome Activated B-Lymphocyte Activated Lymphocyte 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 Etiology HIV HIV Infections HIV Seropositivity HIV-1 Herpesviridae Herpesviridae Infections Human Human Herpesvirus 4 Human Herpesvirus 8 Immune signaling Immunocompromised Host Immunologic Deficiency Syndromes Individual Infection Infectious Agent Inhibition of Cell Proliferation Investigation Kaposi Sarcoma Knowledge Life Link Lymphocyte Lymphoid Cell Lymphoma Lymphoproliferative Disorders M cell Maintenance Malignant Neoplasms Mediating Memory B-Lymphocyte Molecular Molecular Target Nasopharynx Carcinoma Non-Hodgkin&apos s Lymphoma Nuclear Oncogenic Oncolytic Organ Transplantation Oxidative Stress PLK1 gene Patients Persons Phosphotransferases Play Post-Translational Protein Processing Predisposition Primary Infection Process Production Protein-Serine-Threonine Kinases Proteins Proto-Oncogenes Regimen Regulation Reporting Research Rest Risk Risk Factors Role Serine 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 Activation Virus Diseases Virus Latency biological adaptation to stress cancer therapy carcinogenesis chronic infection co-infection effective therapy feasibility testing gammaherpesvirus infected B cell inhibitor kinase inhibitor knock-down large cell Diffuse non-Hodgkin&apos 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

项目摘要

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 γ疱疹病毒感染与许多恶性肿瘤有关，包括B细胞淋巴增生性疾病、胃癌、鼻咽癌。免疫缺陷个体，如因为HIV患者更容易患上γ -疱疹病毒相关的癌症。一般需要几个月在初次感染病毒后，癌症会在几年内出现。这一观察突出了多步骤只有通过病毒持续感染才能实现的致癌过程。EBV和KSHV是γ - 在淋巴细胞中建立潜伏感染并在宿主的余生中维持的疱疹病毒。这些病毒库的间歇性再激活将导致更多病毒的产生和传播。虽然有一些抗病毒药物专门针对γ -疱疹病毒的裂解复制，它们不能消除那些潜在的病毒可能作为病毒相关癌症的危险因素。我们的研究小组最近发现，艾滋病毒感染导致Polo样激酶1（PLK 1）的激活，PLK 1是一种蛋白酶原，癌基因，在B和T细胞淋巴细胞中。PLK 1是一种控制G2-M细胞周期的丝氨酸/苏氨酸激酶在癌症的发展中起重要作用，并且经常在广泛的癌症中过表达。其抑制剂已被开发为很有前途的癌症治疗方法我们进一步发现PLK 1参与调节EBV/KSHV潜伏期，以及它们的细胞库在宿主体内的存活。蛋白质敲除以及PLK 1的化学抑制能使潜伏的EBV/KSHV再活化，并促进γ -疱疹病毒再活化的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使尽管HIV本身并不致癌，但HIV患者患癌症的风险却增加了.我们的调查本课题的研究将通过三个不同的目标来完成，包括：（1）分子水平的研究 EBV/KSHV感染的淋巴细胞中HIV 1激活PLK 1的机制。(2)调查PLK 1如何调节EBV/KSHV潜伏期和维持其细胞库。(3)PLK 1的新抑制这意味着通过消除其细胞储库来根除EBV/KSHV持续感染。总的来说，我们提出的研究将有助于理解艾滋病毒的潜伏期， γ疱疹病毒感染是各种病毒相关癌症的基础。该项目还将有助于鉴定用于治疗HIV和EBV/KSHV感染及其相关恶性肿瘤新分子靶点。