Uncoventional vectors for codon-optimized HIV antigens

描述（由申请人提供）：为了开发一种刺激人类免疫缺陷病毒（HIV）免疫应答的疫苗接种策略，我们提出构建基于血清型26、33和35的腺病毒载体，编码与HIV感染有关的免疫原性蛋白。我们和其他研究小组先前在小鼠和非人灵长类动物模型中证明，直接接种编码多种靶抗原的重组腺病毒（rAd） 5型，可引发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预先存在针对最流行的病毒株的中和抗体。开发有效的抗艾滋病毒DNA疫苗的第二个障碍是，在转导的真核细胞中，艾滋病毒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显示，只有不到10%的受试个体具有针对血清型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，从而在真核细胞中实现高水平表达。因此，我们假设目前使用基于腺病毒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“非常规”重组腺病毒亚型的构建来克服。我们还推测，这些研究应该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.