Human gamma herpes virus DNA vaccines

人γ疱疹病毒包括爱泼斯坦-巴尔病毒（EBV或HHV- 4）和卡波西肉瘤疱疹病毒（KSHV或HHV-8）。两者都是致癌的，并有一个慢性潜伏期的感染，这使得人类宿主终身感染。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卡波西肉瘤（特别是在艾滋病患者），所造成的KSHV，和潜伏的EBV感染发现在正常人或表达在一些淋巴瘤，霍奇金病，鼻咽癌，移植后淋巴组织增生性疾病，传染性单核细胞增多症。根据EBV和KSHV中开放阅读框的数量，可以从超过150种基因产物中选择DNA疫苗的靶点。我们计划开始这个项目（特异性目标1），构建针对四种病毒基因产物的DNA疫苗，TSA（“肿瘤特异性抗原”）：KSHV的拉娜（潜伏相关核抗原）和v-细胞周期蛋白以及EBV的LMP-1（潜伏膜蛋白）和LMP-2A。将在Balb/c小鼠（特定目标2）中评价和开发免疫原性和最佳疫苗接种策略，其中预期使用适当工程化载体和10（3）细胞系抑制转化表型。（LMP-2A可能需要额外的修饰，这是四种TSA中唯一一种未知致癌的TSA。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（具体目标3）。将在棉顶绢毛猴中评估DNA疫苗对EBV诱导的淋巴瘤的抑制。类似地，将在DNA疫苗免疫的恒河猴中评估KSHV消除的加速。这一经验和免疫学评价将有望为一种或多种γ疱疹病毒疫苗在人体中的成功试验做好准备。

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.