INDUCTION OF ANTIVIRAL IMMUNITY

FIRCA的合作起源于H.M.教授的实验室。威斯康星大学麦迪逊分校McArdle癌症研究实验室的Temin。 最初的合作得到了1992年授予Temin博士和Altaner博士的FIRCA奖的支持，在Temin博士去世后，目前的合作基于与Kathleen Boris-Lawrie博士的新实验自发发展-当时是Temin博士实验室的博士后研究员。 FIRCA的合作是Boris-Lawrie博士的创新逆转录病毒载体开发与Altaner博士的动物模型系统的互利互补结合。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）在遗传上相关，并且兔中BLV疾病的快速和确定的过程提供了实验上易于处理的模型来研究复杂逆转录病毒的发病机制。 BLV编码三种常见的逆转录病毒结构/酶蛋白（Gag、Pol、Env）和特征性复杂调节蛋白（Tax、雷克斯）以及致病所必需的辅助蛋白（RIII、GIV）。 我们首次建立了独特的逆转录病毒载体，其独立于这些调节和辅助蛋白复制BLV结构/酶基因。这些结构基因载体（SGV）已被提出作为一个原型的安全和预防性的疫苗，对致病性感染引起的复杂的逆转录病毒。 我们先前的实验验证了BLV SGV具有感染性、免疫原性和缺乏致病性的假设。 结果表明，BLV SGV感染天然BLV靶细胞群，诱导抗BLV抗体，并且与BLV不同，在兔中缺乏致病性。 下一步是检验BLV SGV感染诱导BLV特异性细胞介导的免疫并保护免受致病性BLV感染的假设。在该FIRCA申请中提出的该实验将包括评价新型BLV SGV预防性疫苗接种方法的关键步骤，并提供对BLV调节和辅助基因在BLV免疫应答和发病机制中的作用的重要见解。 未来的计划包括扩展BLV系统的知识，以评估基于HTLV和HIV的相关SGV，这些SGV被认为是针对这些致病性人类逆转录病毒疾病的安全预防性疫苗。

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.