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

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 淋巴组织增生性疾病、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。

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.