Peptide-mediated immunotherapy of KSHV-associated malignancy.

kshv相关恶性肿瘤的肽介导免疫治疗研究领域：5-DE-109治疗HIV/AIDS相关口腔表现和AIDS恶性肿瘤的新型免疫疗法卡波西肉瘤（KS），特别是口服KS，是HIV感染患者癌症的主要原因。虽然在接受HAART治疗的患者中口服KS的发病率有所下降，但人们越来越关注耐药HIV-1毒株的发展和传播，这反过来又导致口腔并发症的再次发生。卡波西肉瘤相关疱疹病毒（KSHV）是诱导KS肿瘤、胸腔积液淋巴瘤和多中心Castleman病的病原。我们最近开发了一种新的灵长类动物模型，该模型显著概括了人类KSHV感染和发病机制的重要方面，从而为开发针对KSHV感染的潜在治疗策略提供了独特的工具。自噬是一种新兴的细胞途径，其中亚细胞膜的动态形态变化导致蛋白质和细胞器的降解。该过程还分别通过降解细胞内微生物和抑制癌细胞生长，在宿主的抗微生物和抗肿瘤反应中发挥作用。我们发现了病毒FLIP短肽诱导自噬死亡的治疗活性。因此，本提案的目标是在培养和异种移植小鼠模型（方法1）和普通狨猴灵长类模型（方法2）中测试vFLIP肽作为治疗kshv相关恶性肿瘤的功效。

DESCRIPTION (provided by applicant): Peptide-mediated immunotherapy of KSHV-associated malignancy Research Area: 5-DE-109 Novel Immunotherapies to Treat HIV/AIDS-related Oral Manifestations and AIDS Malignancies Kaposi sarcoma (KS), specifically oral KS, is the leading cause of cancer in patients with HIV infection. While there is a reduction in the incidence of oral KS among patients receiving HAART, an increasing concern is the development and spread of drug resistant HIV-1 strains, which in turn leads to reoccurrence of oral complication. Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent to induce KS tumors, pleural effusion lymphomas and multicentric Castleman's disease. We have recently developed a new primate model that significantly recapitulates the important aspects of the KSHV infection and pathogenesis of humans, thus providing a unique tool for the development of potential therapeutic strategies against KSHV infection. Autophagy is a new, emerging cellular pathway in which dynamic morphological changes of subcellular membranes leads to the degradation of proteins and organelles. This process also plays a role in the anti-microbial and anti-tumor responses of the host by degrading intracellular microbes and by suppressing cancer cell growth, respectively. We discover the autophagy death- inducing therapeutic activity of the viral FLIP short peptides. Thus, the goal of this proposal is to test the efficacy of the vFLIP peptide as a therapeutic agent against KSHV-associated malignancies in culture and xenografted murine model (Approach1) and in common marmoset primate model (Approach 2). PUBLIC HEALTH RELEVANCE: Kaposi sarcoma (KS), specifically oral KS, is the leading cause of cancer in patients with HIV infection. The goal of this proposal is to test the efficacy of the vFLIP peptide as a therapeutic agent against KSHV-associated malignancies in culture and xenografted murine model and in common marmoset primate model.