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

卡波西肉瘤相关疱疹病毒(KSHV)是一种与免疫系统受损的人患上一种名为卡波西肉瘤(KS)的癌症有关的病毒。KS是南非男性、女性和儿童中发现的前十大癌症之一，在非洲男性中排名第三。尽管如此，目前还没有针对KSHV病毒的特效或有效的治疗方法。由于KS是一种定义为艾滋病的疾病，使用抗逆转录病毒药物控制HIV/AIDS和改善免疫功能已被研究为KS的一种可能的治疗方法。然而，这并不总是有效的，因为许多艾滋病毒感染得到良好控制的患者仍会发展为KS，一些人一旦开始抗逆转录病毒治疗，可能会出现危及生命的副作用。因此，迫切需要有针对性、特异性和有效性的抗KSHV疗法。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，一个是病毒主要处于休眠状态的持续终身感染(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)。对于KSHV来说，独特的是，潜伏的和裂解的复制周期都有助于KSHV相关癌症的发展。因此，研究调节潜伏期和裂解期的病毒-宿主细胞相互作用对于全面了解KSHV相关疾病是非常必要的。此外，抑制任何一个或两个阶段可能提供了一个机会，以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系列蛋白质，称为分子伴侣。KSHV需要分子伴侣来经历潜伏和裂解复制周期，作为病毒功能的广泛宿主细胞因子。分子伴侣本身受被称为辅助伴侣的宿主蛋白家族的调控，辅助蛋白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表明，宿主辅助伴侣STIP1参与了KSHV生物学的多个方面。这项建议将研究STIP1在KSHV潜伏期和裂解期的作用，并开发新的方法来抑制STIP1的S功能，作为KSHV的靶向治疗药物。我们将应用分子病毒学和药物发现相结合的方法，详细描述在KSHV潜伏和裂解复制过程中由STIP1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STIP1功能的分子，这些分子可能随后被开发成KSHV特异性的抗病毒药物。

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.