Human gamma herpes virus DNA vaccines

人类γ疱疹病毒包括eb病毒（EBV或HHV- 4）和卡波西肉瘤疱疹病毒（KSHV或HHV-8）。这两种病毒都具有致癌性，并有慢性感染潜伏期，使人类宿主终生感染。我们希望利用目前对这些病毒的了解来开发DNA疫苗。我们的目的是促进消除或相对抑制由KSHV引起的卡波西氏肉瘤（特别是艾滋病患者），以及在正常人中发现或在某些淋巴瘤、霍奇金病、鼻咽癌、移植后淋巴细胞增生性疾病和传染性单核细胞增多症中表达的潜伏性EBV感染。根据EBV和KSHV中开放阅读框的数量，有150多个基因产物可供选择DNA疫苗的靶标。我们计划通过构建针对四种病毒基因产物的DNA疫苗来开始这个项目（Specific Aim 1）， tsa（“肿瘤特异性抗原”）：LANA（潜伏期相关核抗原）和v-cyclin形式的KSHV和LMP-1（潜伏膜蛋白）和EBV的LMP-2A。将在Balb/c小鼠（Specific Aim 2）中评估和开发免疫原性和最佳疫苗接种策略，其中预期使用带有10(3)细胞系的适当工程载体抑制转化表型。（LMP-2A可能需要额外的修改，它是四种TSAs中唯一一种未知的致癌物质。）最后，为了准备未来的人类研究，我们将在非人类灵长类动物中测试DNA疫苗（特定目标3）。DNA疫苗对eb病毒诱导的淋巴瘤的抑制作用将在棉顶绢毛猴中进行评估。同样，将在DNA疫苗免疫的恒河猴中评估KSHV消除的加速。这一经验和所进行的免疫学评价有望为一种或多种伽玛疱疹病毒疫苗在人体中的成功试验做准备。

Human gamma herpesviruses include Epstein-Barr virus (EBV or HHV- 4) and Kaposi's Sarcoma herpesvirus (KSHV or HHV-8). Both are oncogenic and have a chronic latent phase of infection, which leaves humans hosts infected for life. We hope to adapt the current knowledge of these viruses to develop DNA vaccines. Our purpose is to facilitate the elimination or relative suppression of Kaposi's sarcoma (especially in AIDS patients), as caused by KSHV, and of the latent EBV infection found in normals or expressed in some lymphomas, Hodgkin's disease, nasopharyngeal carcinomas, post-transplant lymphoproliferative disease, and infectious mononucleosis. These are over 150 gene products from which to select the targets for a DNA vaccine, as measured by the number of open reading frames in EBV and KSHV. We plan to begin this project (Specific Aim 1) by constructing DNA vaccines directed against four viral gene products, the TSAs ("tumor specific antigens"): LANA (latency associated nuclear antigen) and v-cyclin form KSHV and LMP-1 ((latent membrane protein) and LMP-2A from EBV. The immunogenicity and optimal vaccination strategy will be evaluated and developed in Balb/c mice (Specific Aim 2), where suppression of the transformed phenotype is expected using appropriately engineered vectors with, the 10(3) cell line. (Additional modifications may be needed for LMP-2A, which is the only one of the four TSAs not known to be oncogenic.) Finally, in preparation for future human studies we will test the DNA vaccines in non-human primates (Specific Aim 3). The suppression of EBV-induced lymphomas by the DNA vaccines will be assessed in Cotton top tamarins. Similarly, the acceleration of KSHV elimination will be assessed in DNA vaccine immunized Rhesus macaques. This experience and the immunologic evaluations performed will hopefully be preparatory for a successful trial of one or more of these gamma herpes virus vaccines in man.