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: 6777003
• 负责人: Alagarsamy Srinivasan
• 金额: $ 21.79万
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777003
• 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的发病机制。此外，这些基因也可以作为治疗和疫苗干预的理想靶点。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”细胞潜伏地感染了HHV-8。HHV-8编码的具有转化潜能的基因[K1，糖蛋白；K9，干扰素调节因子；kaposin K12的;orf73，潜伏期相关抗原（LANA-1）；和orf74（一种vlL-8受体同源物）、kaposin和LANA-1与v-cyclin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点。这促使我们开始将Kaposin和LANA-1作为可能的病毒靶蛋白，用于疫苗方法诱导对HHV-8的免疫。最近在Kaposin中发现的CTL表位进一步支持了这一概念。过去已成功地使用疫苗预防病毒感染（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，我们推测，在其他HHV-8蛋白缺失的情况下，Kaposin和LANA-1的表达可能导致诱导有效和持久的体液和细胞免疫反应，这可能对消除感染HHV-8的细胞和干扰KS的发展有价值。为此，我们提出以下目标：i)生成编码天然和修饰形式的Kaposin和LANA-1的DNA疫苗载体。ii)以小鼠为动物模型，表征对Kaposin和LANA-1的细胞和体液免疫反应；iii)增强对Kaposin免疫反应的策略；iv)以表达病毒蛋白的肿瘤细胞为攻毒模型，评估潜伏基因诱导的保护水平。这些研究的结果可能为进一步探索开发针对HHV-8的疫苗提供基线信息。