Uncoventional vectors for codon-optimized HIV antigens

描述(申请人提供)：为了开发一种疫苗接种策略来刺激对人类免疫缺陷病毒(HIV)的免疫反应，我们建议构建基于26、33和35血清型编码HIV感染相关免疫原蛋白的腺病毒载体。我们和其他团队以前已经在小鼠和非人类灵长类动物模型中证明，直接接种编码各种靶抗原的重组腺病毒(RAD)5型可引起针对转基因产物的强烈特异性免疫反应(见附录1-4)。目前，人类Rad免疫策略的一个主要限制是针对最流行的病毒株的中和抗体的普遍存在。开发有效的抗HIV DNA疫苗的第二个障碍是在转导的真核细胞中HIV编码蛋白的表达水平很低。然而，有趣的是，在亚洲和北美人群中进行的初步研究表明，只有不到10%的受试者具有对腺病毒血清型26、33或35的中和抗体。此外，我们和其他人已经能够优化SIV和HIV抗原序列的密码子，从而在真核细胞中高效表达。因此，我们假设，目前使用腺病毒5型活疫苗载体的技术限制可以通过实施基于整合密码子优化的HIV抗原cDNA的“非传统”重组腺病毒亚型的构建来克服。我们还推测，这些研究应该会导致更有效的疫苗接种策略，旨在治疗获得性免疫缺陷障碍。

DESCRIPTION (provided by applicant): In order to develop a vaccination strategy for stimulating the immune response against Human Immunodeficiency Virus (HIV), we propose to construct adenoviral vectors based on serotypes 26, 33 and 35 encoding immunogenic proteins involved in HIV infection. We and other groups have demonstrated previously in murine and non human primate models that direct vaccination with recombinant adenovirus (rAd) type 5 encoding a variety of target antigens elicits strong specific immune responses against the transgene products (see Appendix 1-4). Currently, a major limitation to rAd immunization strategies in humans is the preexistence of neutralizing antibodies directed against the most prevalent strains of the virus. A second hurdle towards the development of an effective anti-HIV DNA vaccine has been the poor expression level of HIV-encoded proteins in transduced eukaryotic cells. Interestingly, however, preliminary studies conducted in Asian and North American populations have revealed that less than 10% of tested individuals have neutralizing antibodies against adenovirus serotypes 26, 33 or 35. Moreover, we and others have been able to optimize the codon of SIV and HIV antigenic sequences, resulting in high level expression in eukaryotic cells. Hence, we hypothesize that the current technical limitations of using adenovirus type 5-based live vaccine vectors may be overcome by implementing constructs based on "unconventional" recombinant adenoviral subtypes that integrate codon-optimized HIV antigen cDNAs. We also speculate that these studies should lead to more effective vaccination strategies designed to treat acquired immunodeficency disorders.