Kaposin and LANA-1 of HHV8 as vaccine targets

描述(由申请人提供)：鉴于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，这些基因也可能成为治疗和疫苗干预的理想靶点。为此，我们考虑了潜伏期表达的HHV-8基因，因为KS和B细胞的肿瘤梭形细胞潜伏着感染HHV-8。在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；K12，Kaposin；orf73，潜伏期相关抗原(LANA-1)；orf74，Vll-8受体同源物]中，Kaposin和LANA-1在潜伏感染的细胞中与v-Cyclin和v-Flip一起转录。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。这促使我们开始研究Kaposin和LANA-1，作为疫苗诱导对HHV-8免疫的可能病毒目标蛋白。最近在Kaposin中展示的CTL表位进一步支持了这一概念。过去，疫苗已成功用于预防病毒感染(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反应和细胞反应。在此基础上，我们推测Kaposin和LANA-1的表达，在没有其他HHV-8蛋白的情况下，可能导致诱导有效而持久的体液和细胞免疫反应，这可能在消除感染HHV-8的细胞和干扰KS的发展方面有价值。为此，我们提出了以下目标：i)构建编码Kaposin和LANA-1天然和修饰形式的DNA疫苗载体。Ii)以小鼠为动物模型表征针对Kaposin和LANA-1的细胞和体液免疫反应，iii)增强对Kaposin的免疫反应的策略，以及iv)以表达病毒蛋白的肿瘤细胞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。

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.