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）：鉴于HHV-8的致癌能力，已经提出，对诱导细胞转化的病毒基因的理解可能有助于阐明KS发病机理。此外，此类基因也可以作为治疗和疫苗干预措施的理想靶标。 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）;疫苗的病毒靶蛋白可能会诱导HHV-8的免疫力。基于此，我们假设Kaposin和Lana-1的表达在没有其他HHV-8蛋白的情况下可能导致诱导有效且持久的体液和细胞免疫反应，这可能在消除被HHV-8感染的细胞中具有价值，并影响KS的发育。在此方面，我们提出以下目的：i）生成编码Kaposin和Lana-1的天然和改良形式的DNA疫苗向量。 ii）表征使用小鼠作为动物模型对Kaposin和Lana-1的细胞和体液免疫反应，iii）增强针对Kaposin的免疫反应的策略，以及IV），以评估使用表达病毒蛋白作为挑战模型的潜在基因引起的潜在基因诱导的保护水平。这些研究的结果可能会提供基线信息，以进一步探索针对HHV-8的疫苗开发。