Kaposin and LANA-1 of HHV8 as vaccine targets

HHV8 的卡波辛和 LANA-1 作为疫苗靶标

• 批准号: 6696091
• 负责人: Alagarsamy Srinivasan
• 金额: $ 23.27万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696091
• 关键词: B lymphocyte; HeLa cells; Herpesviridae vaccine; Kaposi's sarcoma; MHC class I antigen; antigen antibody reaction; biotechnology; cell surface receptors; cell transformation; cellular immunity; chimeric proteins; human herpesvirus 8; humoral immunity; laboratory mouse; latent virus infection; neoplasm /cancer immunology; neoplastic process; receptor expression; tissue /cell culture; transfection /expression vector; vaccine development; vaccinia virus; virus antigen; virus genetics; virus protein

DESCRIPTION (provided by applicant): Given the oncogenic capabilities of HHV-8, it has been suggested that an understanding of the viral genes with the potential to induce transformation of cells may contribute towards the elucidation of KS pathogenesis. In addition, such genes may also serve as ideal targets for both therapeutic and vaccine interventions. For this purpose, we have considered HHV-8 genes which are expressed during latency, as tumor 'spindle" cells of KS and B-cells are latently infected with HHV-8. Of the genes encoded by HHV-8 with transformation potential [K1, glycoprotein; k9, interferon regulatory factor; K12, kaposin; orf73, latency-associated antigen (LANA-1); and orf74, a vlL-8 receptor homolog ], kaposin and LANA-1 are transcribed in latently infected cells along with v-cyclin and v-FLIP. Both v-cyclin and v-FLIP are viral homologs of cellular genes and thus may not be suitable as targets for vaccine strategies due to autoimmunity. This has prompted us to initiate work on Kaposin and LANA-1 as the likely viral target proteins for vaccine approaches to induce immunity against HHV-8. The recent demonstration of CTL epitopes in Kaposin further lends supports to this concept. Vaccines have been successfully used against viral infections (smallpox, polio, varicella) in the past and the correlates of protective immunity may include both the humoral and cellular responses. Based on this, we hypothesize that the expression of Kaposin and LANA-1, in the absence of other HHV-8 proteins, may lead to an induction of potent and durable humoral and cellular immune responses which may be of value in eliminating cells infected with HHV-8 and interfering with the development of KS. Towards this, we propose the following aims: i) to generate DNA vaccine vectors encoding native and modified forms of Kaposin and LANA-1. ii) Characterize the cellular and humoral immune responses against Kaposin and LANA-1 using mice as the animal model, iii) Strategies to enhance the immune responses against Kaposin, and iv) to assess the level of protection induced by latent genes using tumor cells expressing viral proteins as the challenge model. The results from these studies are likely to provide baseline information for further exploration in the development of vaccines against HHV-8.

描述（由申请人提供）：考虑到 HHV-8 的致癌能力，有人建议了解具有诱导细胞转化潜力的病毒基因可能有助于阐明 KS 发病机制。此外，此类基因还可以作为治疗和疫苗干预的理想靶标。为此，我们考虑了在潜伏期表达的 HHV-8 基因，因为 KS 和 B 细胞的肿瘤“纺锤体”细胞潜伏感染 HHV-8。在 HHV-8 编码的具有转化潜力的基因中 [K1，糖蛋白；k9，干扰素调节因子；K12，卡波蛋白；orf73，潜伏期相关抗原 （LANA-1）；和orf74（vlL-8受体同源物）、卡波蛋白和LANA-1与v-细胞周期蛋白和v-FLIP一起在潜伏感染的细胞中转录。 v-cyclin 和 v-FLIP 都是细胞基因的病毒同源物，因此由于自身免疫，可能不适合作为疫苗策略的靶标。这促使我们开始研究卡波辛和 LANA-1 作为 可能用于疫苗方法的病毒靶蛋白，以诱导针对 HHV-8 的免疫力。最近卡波辛中 CTL 表位的证明进一步支持了这一概念。过去，疫苗已成功用于对抗病毒感染（天花、脊髓灰质炎、水痘），保护性免疫的相关因素可能包括体液和细胞反应。基于此，我们假设表达式 在没有其他 HHV-8 蛋白的情况下，卡波辛和 LANA-1 可能会诱导有效且持久的体液和细胞免疫反应，这可能有助于消除感染 HHV-8 的细胞并干扰 KS 的发展。为此，我们提出以下目标：i) 生成编码天然和修饰形式的卡波辛和 LANA-1 的 DNA 疫苗载体。 ii) 使用小鼠作为动物模型来表征针对卡波辛和 LANA-1 的细胞和体液免疫反应，iii) 增强针对卡波辛免疫反应的策略，以及 iv) 使用表达病毒蛋白的肿瘤细胞作为攻击模型来评估潜在基因诱导的保护水平。这些研究的结果可能为进一步探索 HHV-8 疫苗的开发提供基线信息。