Recombinant Papillomavirus-based HIV Vaccine Targeting Genital Mucosa

针对生殖器粘膜的基于重组乳头瘤病毒的 HIV 疫苗

• 批准号: 8993591
• 负责人: Marie-Claire Elisabeth Gauduin
• 金额: $ 27.75万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-25 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993591
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Antigens; Attenuated; B-Lymphocytes; Biopsy; Blood; Cell Culture Techniques; Cytomegalovirus; Development; Electron Microscopy; Elements; Epithelial Cells; Epitopes; Female; Gene Delivery; Gene Expression; Genital system; Genome; HIV; HIV vaccine; Human; Human Papillomavirus; Immune response; Immune system; Immunity; Immunization; Immunologic Techniques; In Vitro; Infection; Infection prevention; Laboratories; Lead; Length; Life; Macaca; Macaca mulatta; Methodology; Modeling; Molecular; Molecular Biology Techniques; Monitor; Mucous Membrane; Nature; Organ; Organism; Papillomavirus; Plasmids; Recombinant DNA; Recombinants; Research; Route; SIV; SIV Vaccines; Safety; Site; Staging; Stem cells; Surface; System; T cell response; T-Lymphocyte Epitopes; Testing; Transfection; Vaccinated; Vaccines; Vagina; Viral; Viral Antigens; Viral Vector; Virus; Virus Diseases; Virus Replication; Virus-like particle; Work; base; design; env Genes; gene delivery system; genetic vaccine; immunogenic; improved; in vivo; mucosal site; novel; novel vaccines; particle; prevent; public health relevance; seroconversion; success; transmission process; vaccine development; vector

 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.

 描述（适用提供）：在HIV疫苗领域进行二十年的研究表明，使用复制病毒刺激免疫系统是开发疫苗的最佳希望之一。最近，基于巨细胞病毒的疫苗策略成功地保护了一半的动物接种疫苗。但是，需要提高这种成功率，特别是通过使用限制进入粘膜入境门户的HIV复制的活病毒媒介。在病毒传播的初始阶段，粘膜组织中的体液和细胞免疫调查会阻塞或包含复制的能力可能对疫苗接种宿主抵抗感染的能力产生深远的影响。理想的疫苗应用病毒抗原对免疫系统进行救生刺激，并应将免疫激发聚焦于HIV的主要复制部位。 疫苗发育中最近的突破已使用高度免疫原性病毒（例如颗粒（VLP））作为抗原载体来刺激免疫系统。对于乳头瘤病毒（PV）尤其如此。这些VLP也可用于封装完全感染的PV基因组或表达质粒。这些颗粒在细胞培养和体内都具有感染性。已经从恒河猕猴中分离出一种称为RHPV的PV，从而有机会将PV作为SIV抗原矢量进行测试。我们的合作者最近成功地使用了假型RHPV来接种恒河猕猴，从而有可能在不感染的情况下操纵该病毒。 在猕猴中，将RHPV用作SIV疫苗是研究HPV作为人类抗HIV疫苗潜力的最佳模型。因此，R21的具体目的将是：1）设计和优化RHPV载体，该载体导致SIV抗原在恒河猕猴中长期表达，该猕猴通过阴道，途径疫苗接种； 2）用嵌合RHPV/SIV实验感染雌性猕猴，并研究诱导的免疫反应的性质。我们的工作应为使用乳头瘤病毒作为粘膜输送系统开发HIV疫苗的“概念证明”，以引起对HIV感染的长期保护。