Recombinant Papillomavirus-based HIV Vaccine Targeting Genital Mucosa

 描述(申请人提供)：二十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。我们的合作者最近成功地使用假型RhPV接种恒河猴，使我们有可能在不丧失传染性的情况下操纵这种病毒。 在猕猴体内使用人乳头瘤病毒作为SIV疫苗将是研究HPV作为人类抗HIV疫苗潜力的最佳模型。因此，R21的具体目标将是：1)设计和优化RhPV载体，使SIV抗原在经阴道免疫的恒河猴体内长期表达；以及，2)实验用嵌合的RhPV/SIV感染雌性猕猴，并研究其诱导的免疫反应的性质。我们的工作应该为使用乳头瘤病毒作为粘膜递送系统的艾滋病毒疫苗的开发提供一种“概念验证”，以获得对艾滋病毒感染的长期保护。

 DESCRIPTION (provided by applicant): 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 viruses 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. Our collaborator has recently been using pseudotyped RhPV successfully to inoculate Rhesus macaques giving the possibility to manipulate this virus without losing infectivity. The use of RhPV as a SIV vaccine in macaque will be the best model possible to investigate the potential of HPV as an anti-HIV vaccine in human. Therefore, specific aims of the R21 will be: 1) To design and optimize a RhPV vector that leads to long-term expression of SIV antigens in rhesus macaques vaccinated by vaginal, route; and, 2) To experimentally infect female macaques with a chimeric RhPV/SIV and investigate the nature of the immune responses induced. Our work should provide a "proof-of-concept" for the development of HIV vaccines using the papillomavirus as a delivery system at the mucosa to elicit long-term protection against HIV infection.