Trans-complementing papillioma virus for AIDS vaccine

 描述(申请人提供)：二十多年来艾滋病毒疫苗领域的研究表明，使用复制病毒来刺激免疫系统是我们开发疫苗的最大希望之一。最近，一种基于巨细胞病毒的疫苗策略成功地保护了一半接种疫苗的动物。然而，这一成功率需要提高，特别是通过使用活病毒载体来限制进入粘膜入口的艾滋病毒复制。在病毒传播的初始阶段，粘膜组织中体液和细胞免疫反应阻止或遏制复制的能力可能对接种疫苗的宿主抵抗感染的能力有深远的影响。一种理想的疫苗应该用病毒抗原对免疫系统提供终身刺激，并将免疫反应集中在艾滋病毒的主要复制部位。 最近在疫苗开发方面的突破使用了高度免疫原性的病毒样颗粒(VLP)作为抗原载体来刺激免疫系统。对于乳头瘤病毒(PV)来说尤其如此。这些VLP还可用于包裹完全具有感染性的PV基因组或表达质粒。这些颗粒在细胞培养和体内都是有感染力的。从一只恒河猴中分离出一种名为RhPV的PV，这为将PV作为SIV抗原载体进行测试提供了机会。假型人乳头瘤病毒最近被我们的合作者用来成功地接种恒河猴，这使我们有可能在不失去传染性的情况下操纵这种病毒。 在猕猴体内使用RPV作为SIV疫苗，然后进行SIVmac挑战，将是研究HPV作为人类抗HIV疫苗潜力的最佳模式。然而，RhPV的有限包装能力导致我们提出了一种全新的活疫苗策略，该策略基于反式补充性乳头瘤病毒的黏膜感染，该策略仍然具有复制性，并将在较长一段时间内促进口腔、直肠和阴道粘膜中抗体的产生和抗SIV中央记忆CD8 T细胞的扩张。因此，该建议的具体目的将是：1)设计一种能够在阴道、直肠和/或口服途径接种SIV抗原的恒河猴体内长期表达SIV抗原的RhPV载体；2)通过实验感染雌性恒河猴并研究这种反式互补的RhPV/SIV载体在12个月内诱导的免疫反应的性质和安全性；以及3)研究反式互补的RHPV/SIV疫苗在经阴道或直肠内攻击多个低剂量同源SIV毒株后的保护效果。我们的工作应该提供一种“概念验证”，在这种情况下，我们将质疑作为疫苗载体的RhPV在生殖器部位产生强大和长期的抗SIV免疫的能力。

 DESCRIPTION (provided by applicant): Over twenty years of research in the field of HIV vaccine have shown that the use of replicating virus to stimulate the immune system is one of our best hopes to develop a vaccine. Recently a cytomegalovirus-based vaccine strategy has successfully protected half of the animals vaccinated. However, this success rate needs to be improved, notably by the use of live viral vectors that restrict HIV replication at the mucosal portal of entry. The capacity of humoral and cellular immune responses in mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound impact on the ability of a vaccinated host to resist infection. An ideal vaccine should provide a life-lon stimulation of the immune system with viral antigens and should focus the immune response at the site of primary replication of HIV. Recent breakthroughs in vaccine development have used highly immunogenic virus-like particles (VLP) as antigen carriers to stimulate the immune system. This is particularly true for Papillomaviruses (PV). These VLP can also be used to encapsidate either fully infectious PV genome or expression plasmids. These particles are infectious both in cell culture and in vivo. A PV called RhPV has been isolated from a Rhesus macaque giving the opportunity to test PV as SIV antigen vectors. Pseudotyped RhPV has recently been used by our collaborator to successfully inoculate Rhesus macaques giving the possibility to manipulate this virus without losing infectivity. The use of RhPV as a SIV vaccine in macaque followed by SIVmac challenge will be the best model possible to investigate the potential of HPV as an anti-HIV vaccine in humans. However the limiting packaging capacity of RhPV leads us to propose a completely new live vaccine strategy based on mucosal infection with trans-complementing papillomavirus that would still be replicative and would promote antibody production and anti-SIV central memory CD8+ T cells expansion at the oral, rectal and vaginal mucosa for a prolonged period of time. Therefore, specific aims of proposal will be: 1) To design a RhPV vector that leads to long-term expression of SIV antigens in rhesus macaques vaccinated by vaginal, rectal and/or oral routes; 2) To experimentally infect female macaques with this trans-complementing RhPV/SIV vector and investigate the nature of the immune responses induced and safety over 12 months; and, 3) To investigate the protective efficacy of the trans-complementing RHPV/SIV vaccine following intravaginal or intrarectal challenge with multiple low-dose homologous SIV strains challenge. Our work should provide a "proof-of-concept" in which we will question the capacity of RhPV, as a vaccine vector, to generate strong and long-term anti-SIV immunity at the genital site.