INDUCTION OF ANTIVIRAL IMMUNITY

FIRCA的这项合作始于威斯康星大学麦迪逊分校麦卡德尔癌症研究实验室H.M.特明教授的实验室。最初的合作得到了1992年FIRCA授予特明博士和阿尔塔纳博士的奖项的支持，在特明博士去世后，目前的合作自发地基于与凯瑟琳·鲍里斯-劳里博士--当时在特明博士实验室的博士后研究员-进行的新实验而发展。FIRCA的这项合作是Boris-Lawrie博士创新的逆转录病毒载体开发与Altaner博士的动物模型系统的互惠互补的结合。牛白血病病毒(BLV)是一种基因复杂的逆转录病毒，是引起牛地方性持续性淋巴细胞增多症和淋巴肉瘤的病原体。BLV与人类T细胞白血病病毒(HTLV)和人类免疫缺陷病毒(HIV)有基因上的亲缘关系，而BLV在兔体内快速明确的发病过程为研究复杂逆转录病毒的致病机制提供了一个实验上容易追踪的模型。BLV编码三种常见的逆转录病毒结构/酶蛋白(Gag、Pol、Env)和特征复杂的调节蛋白(Tax、Rex)和辅助蛋白(RIII、GIV)，这些都是致病所必需的。我们首次建立了独特的逆转录病毒载体，可以复制BLV的结构/酶基因，而不依赖于这些调节蛋白和辅助蛋白。这些结构基因载体(SGV)已被提出作为预防复杂逆转录病毒引起的病原性感染的安全和预防性疫苗的原型。我们以前的实验证实了BLV SGV具有传染性、免疫原性和无致病性的假设。结果表明，BLV SGV能感染自然BLV靶细胞群，诱导产生抗BLV抗体，与BLV不同，对兔无致病性。下一步是验证BLV SGV感染诱导BLV特异性细胞免疫并保护BLV免受致病性BLV感染的假设。FIRCA申请中提出的这些实验将是评估新型BLV SGV预防性疫苗接种方法的关键一步，并为BLV调节基因和辅助基因在BLV免疫反应和致病机制中的作用提供重要的见解。未来的计划包括扩展来自BLV系统的知识，以评估基于HTLV和HIV的相关SGV，这些疫苗被认为是安全的、预防这些致病性人类逆转录病毒疾病的疫苗。

This FIRCA collaboration originated in the laboratory of Prof. H.M. Temin at McArdle Laboratory for Cancer Research, University of Wisconsin-Madison. The initial collaboration was supported by a FIRCA award to Dr. Temin and Dr. Altaner in 1992, and after Dr. Temin's decease, the present collaboration spontaneously evolved based on new experiments with Dr. Kathleen Boris-Lawrie -that time post-doctoral fellow in Dr. Temin's laboratory. This FIRCA collaboration is a mutually beneficial and complementary combination of Dr. Boris-Lawrie's innovative retrovirus vector development with Dr. Altaner's animal model system. Bovine leukemia virus (BLV) is a genetically complex retrovirus and the etiologic agent of enzootic persistent lymphocytosis and lymphosarcoma in cattle. BLV is genetically related to human T-cell leukemia virus (HTLV) and to human immunodeficiency virus (HIV), and the rapid and definitive course of BLV disease in rabbits provides an experimentally tractable model to study pathogenesis of complex retroviruses. BLV encodes the three common retroviral structural/enzymatic proteins (Gag, Pol, Env) and characteristic complex regulatory proteins (Tax, Rex) and accessory proteins (RIII, GIV) that are necessary for pathogenesis. We have established for the first-time unique retrovirus vectors that replicate the BLV structural/enzymatic genes independently of these regulatory and accessory proteins. These structural gene vectors (SGV) have been proposed as a prototype safe and preventative vaccine against pathogenic infection caused by complex retroviruses. Our previous experiments validated the hypothesis that the BLV SGVs are infectious, immunogenic, and lack pathogenicity. The results demonstrated that BLV SGV infect the natural BLV target cell population, induce anti-BLV antibodies, and unlike BLV, lack pathogenicity in rabbits. The next step is to test the hypothesis that infection with BLV SGV induces BLV-specific cell- mediated immunity and protects against pathogenic BLV infection. This experiments proposed in this FIRCA application will comprise a critical step in the evaluation of the novel BLV SGV preventative vaccination approach and provide important insight into the role of BLV regulatory and accessory genes in BLV immune response and pathogenesis. Future plans include extension of knowledge from the BLV system to evaluate related SGV based on HTLV and HIV that are postulated to be safe, preventative vaccines against these pathogenic human retroviral disease.