Human gamma herpes virus DNA vaccines

人类伽玛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，都有一个慢性潜伏期感染，这会让人类宿主终身感染。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由KSHV引起的卡波西肉瘤(尤其是艾滋病患者)，以及在正常人中发现的或在一些淋巴瘤、霍奇金病、鼻咽癌、移植后淋巴增生性疾病和传染性单核细胞增多症中表达的潜伏的EBV感染。根据EBV和KSHV中开放阅读框的数量，这些超过150种基因产品可用于选择DNA疫苗的靶标。我们计划首先构建针对四种病毒基因产物的DNA疫苗，TSA(肿瘤特异性抗原)：LANA(潜伏相关核抗原)和v-Cyclin形式KSHV和LMP-1(潜伏膜蛋白)和来自EBV的LMP-2A。免疫原性和最佳疫苗策略将在Balb/c小鼠(特异性目标2)中进行评估和开发，预计将使用适当的工程载体与10(3)细胞系一起抑制转化的表型。(LMP-2A可能需要额外的修饰，它是四种TSA中唯一一种未知致癌的。)最后，在为未来的人类研究做准备时，我们将在非人类灵长类动物中测试DNA疫苗(具体目标3)。DNA疫苗对EBV诱导的淋巴瘤的抑制作用将在Cotton top Tamarins中进行评估。同样，KSHV消除的加速将在DNA疫苗免疫的恒河猴中进行评估。这一经验和进行的免疫学评估有望为一种或多种伽玛疱疹病毒疫苗在人类身上的成功试验做准备。

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.