Host-virus interactions in KSHV-related malignancies: evaluating the role of STIP1 as a therapeutic target

KSHV 相关恶性肿瘤中宿主病毒的相互作用：评估 STIP1 作为治疗靶点的作用

• 批准号: MR/V030701/1
• 负责人: Adrienne Edkins
• 金额: $ 97.35万
• 依托单位: Rhodes University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV030701%2F1
• 关键词: Host; virus; interactions; KSHV; related

Kaposi's sarcoma-associated herpesvirus (KSHV) is a virus that is linked to the development of a type of cancer known as Kaposi's sarcoma (KS) in individuals with compromised immune systems. KS is one of the top 10 cancers identified in men, women and children in South Africa, where it is the third most common cancer in African men. Despite this, there are no specific or effective treatments for KS that target the KSHV virus directly. As KS is an AIDS-defining disease, controlling HIV/AIDS and improving immune function using antiretroviral agents has been investigated as a possible treatment for KS. However, this is not always effective as many patients with well-controlled HIV infection still develop KS, and some individuals can experience life-threatening side-effects once they start antiretroviral therapy. Consequently, focused, specific and effective anti-KSHV therapies are urgently needed. KSHV is a member of the herpesvirus family and has two distinct life cycles in cells, a persistent life-long infection where the virus is mainly dormant (known as latency) and an infectious cycle that produces new viruses from the host cells (known as lytic replication). Uniquely for KSHV, both the latent and lytic replication cycles contribute to the development of KSHV-associated cancers. Therefore, it is essential to study the virus-host cell interactions which regulate both latent and lytic phases to fully understand KSHV-related disease. Moreover, inhibiting either or both phases may provide an opportunity to develop novel antiviral strategies to inhibit KS formation. This project focuses on a family of proteins found in host cells known as molecular chaperones. Molecular chaperones are needed for KSHV to undergo both latent and lytic replication cycles, acting as broad host cell factors for viral function. Molecular chaperones are themselves regulated by a family of host proteins known as co-chaperones, which are accessory proteins that fine-tune the function of chaperone systems. We have exciting preliminary data implicating the host co-chaperone STIP1 in multiple aspects of KSHV biology. This proposal will investigate how STIP1 functions during the KSHV latent and lytic phases and develop new ways to inhibit STIP1's function for use as KSHV-targeted therapeutics. We will apply a combination of molecular virology and drug discovery to describe in detail the viral and human cell processes controlled by STIP1 during KSHV latency and lytic replication. We will then use that information to design molecules capable of inhibiting STIP1 function in KSHV, which could subsequently be developed into KSHV-specific antivirals in future.

卡波西肉瘤相关疱疹病毒（KSHV）是一种与免疫系统受损的个体中称为卡波西肉瘤（KS）的癌症类型的发展有关的病毒。KS是南非男性、女性和儿童中发现的十大癌症之一，是非洲男性中第三常见的癌症。尽管如此，目前还没有直接针对KSHV病毒的特异性或有效的KS治疗方法。由于KS是一种艾滋病定义的疾病，控制艾滋病毒/艾滋病和改善免疫功能，使用抗逆转录病毒药物已被研究作为一种可能的治疗KS。然而，这并不总是有效的，因为许多控制良好的HIV感染患者仍然会发展KS，并且一旦开始抗逆转录病毒治疗，一些人可能会经历危及生命的副作用。因此，迫切需要有针对性、特异性和有效的抗KSHV治疗。KSHV是疱疹病毒家族的成员，在细胞中有两个不同的生命周期，一个是持续的终身感染，其中病毒主要处于休眠状态（称为潜伏期），另一个是从宿主细胞产生新病毒的感染周期（称为裂解复制）。KSHV的独特之处在于，潜伏性和裂解性复制周期都有助于KSHV相关癌症的发展。因此，有必要研究病毒-宿主细胞相互作用，调节潜伏期和裂解期，以充分了解KSHV相关疾病。此外，抑制其中一个或两个阶段可以提供一个机会，开发新的抗病毒策略，以抑制KS的形成。这个项目的重点是在宿主细胞中发现的一个蛋白质家族，称为分子伴侣。KSHV需要分子伴侣进行潜伏和裂解复制循环，作为病毒功能的广泛宿主细胞因子。分子伴侣本身由称为辅伴侣的宿主蛋白家族调节，辅伴侣是微调伴侣系统功能的辅助蛋白。我们有令人兴奋的初步数据，涉及宿主共伴侣STIP 1在KSHV生物学的多个方面。该提案将研究STIP 1在KSHV潜伏期和裂解期的功能，并开发新的方法来抑制STIP 1的功能，用作KSHV靶向治疗。我们将结合分子病毒学和药物发现来详细描述KSHV潜伏期和裂解性复制期间STIP 1控制的病毒和人类细胞过程。然后，我们将利用这些信息来设计能够抑制KSHV中STIP 1功能的分子，这些分子随后可以在未来开发成KSHV特异性抗病毒药物。