Peptide-mediated immunotherapy of KSHV-associated malignancy.

描述(申请人提供)：多肽介导的KSHV相关恶性肿瘤的免疫疗法研究领域：治疗艾滋病毒/艾滋病相关口腔症状和艾滋病恶性肿瘤的5-DE-109新型免疫疗法卡波西肉瘤(KS)，特别是口腔KS，是艾滋病毒感染患者中癌症的主要原因。虽然接受HAART的患者中口腔KS的发生率有所下降，但人们越来越担心耐药HIV-1毒株的发展和传播，这反过来又会导致口腔并发症的复发。卡波西肉瘤相关疱疹病毒(KSHV)是引起KS肿瘤、胸腔积液淋巴瘤和多中心性Castleman病的病原体。我们最近开发了一种新的灵长类动物模型，它显著概括了KSHV感染和人类发病机制的重要方面，从而为开发潜在的治疗策略提供了一个独特的工具。自噬是一种新的、新兴的细胞途径，亚细胞膜的动态形态变化导致蛋白质和细胞器的降解。这一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。我们发现了病毒翻转短肽的自噬诱导死亡治疗活性。因此，这项建议的目的是在培养和异种移植小鼠模型(接近1)和普通绒猴灵长类动物模型(方法2)中测试vFLIP多肽作为治疗剂对KSHV相关恶性肿瘤的疗效。 公共卫生相关性：卡波西肉瘤(KS)，特别是口腔KS，是艾滋病毒感染患者癌症的主要原因。本提案的目的是在培养和异种移植小鼠模型以及普通绒猴灵长类动物模型中测试vFLIP多肽作为治疗剂对KSHV相关恶性肿瘤的疗效。

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.