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：
10403994
负责人：
Netty G Santoso
金额：
$ 38.85万
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/10403994
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&apos s Lymphoma Nuclear Oncogenic Oncolytic Organ Transplantation Oxidative Stress PLK1 gene Patients Persons 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 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.

项目总结