Mucosal Protection Against HIV Generated by PIV5 Priming and VLP Boosting

PIV5 启动和 VLP 增强产生的针对 HIV 的粘膜保护

• 批准号: 8706630
• 负责人: Biao He
• 金额: $ 68.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706630
• 关键词: Antigens; Binding; Blood Circulation; Canis familiaris; Cells; Characteristics; Child; Coughing; Cross Presentation; Development; Disease; Dose; Engineering; Event; Exposure to; Failure; Gagging; Genes; Genetic; Goals; HIV; HIV Antigens; HIV Infections; HIV vaccine; Human; Human Cell Line; Immune; Immune response; Immunization; Immunoglobulin A; Immunoglobulin G; Individual; Infection; Infection prevention; Influenza A virus; Influenza Hemagglutinin; Intestines; Intramuscular; Life; Lymphoid Tissue; M cell; Macaca; Membrane; Modality; Modeling; Monkeys; Mucosal Immune Responses; Mucous Membrane; Mus; Paramyxovirus; Particulate; Peptides; Prevention; Preventive; Production; Recombinants; Rectum; Regimen; Role; Route; SIV; Site; Structural Genes; Testing; Vaccination; Vaccine Antigen; Vaccines; Virus; Virus Replication; Virus-like particle; base; design; efficacy testing; immunogenic; mucosa-associated lymphoid tissue; mucosal site; mucosal vaccination; neutralizing antibody; novel; novel strategies; parainfluenza virus; pathogen; prevent; protective efficacy; public health relevance; rectal; research study; response; vaccination strategy; vaccine candidate; vaccine development; vector; vector vaccine

New approaches are needed to develop an effective vaccine for the prevention of HIV infection. Among the major challenges faced in designing an effective vaccine is the genetic variability of the virus and its ability to rapidly escape immune responses once it has disseminated within the infected host. HIV is most frequently acquired via mucosal exposure through sexual contact. Studies in macaques and humans have shown that SIV or HIV initially replicates locally in mucosal tissues prior to disseminating to lymphoid tissues throughout the body through the bloodstream. A vaccine that acts during early events following exposure at the local mucosal site may be more effective in limiting or preventing virus replication and subsequent dissemination. This application will take an approach to eliciting local mucosal immune responses through vaccination with parainfluenza virus type 5 (PIV5) vectors expressing SIV Gag and HIV Env and through mucosal application of Gag-Env virus-like particles (VLPs) engineered to reach the rectal mucosa- associated lymphoid tissue. PIV5 has not previously been evaluated as an HIV vaccine candidate, and is attractive due to its mucosal application and proven ability to protect at mucosal sites for other pathogens. Experiments in this proposal will define the ideal route to elicit potent intrarectal immune responses in mice and macaques. A low-dose intrarectal challenge experiment will be performed in macaques following mucosal immunization with PIV5 and rectal or intramuscular boosting with VLPs. These experiments will determine if vectors designed to stimulate potent local response in the rectal mucosa are protective from SHIV infection, and will seek to define correlates of mucosal immune protection.

需要新的方法来开发预防艾滋病毒感染的有效疫苗。中 设计有效疫苗所面临的主要挑战是病毒的遗传变异性及其 一旦它在受感染的宿主中传播，就能迅速逃避免疫反应。艾滋病是最 通常通过性接触的粘膜接触获得。对猕猴和人类的研究表明， 表明SIV或HIV最初在粘膜组织中局部复制，然后传播到淋巴组织 通过血液流到全身。一种疫苗，在暴露后的早期事件中起作用， 局部粘膜部位可能更有效地限制或防止病毒复制 传播。本申请将采取一种方法来引发局部粘膜免疫反应， 用表达SIV Gag和HIV Env的5型副流感病毒（PIV 5）载体进行疫苗接种， 粘膜应用Gag-Env病毒样颗粒（VLP）工程化以到达直肠粘膜- 相关淋巴组织PIV 5以前没有被评估为HIV候选疫苗， 由于其粘膜应用和已证实的在粘膜部位保护其他病原体的能力而具有吸引力。 这项提议的实验将确定引发小鼠有效直肠内免疫应答的理想途径 和猕猴。将在猕猴中进行低剂量直肠内激发实验， 用PIV 5粘膜免疫和用VLP直肠或肌内加强。这些实验将 确定设计用于刺激直肠粘膜有效局部反应的载体是否具有保护作用， SHIV感染，并将寻求定义粘膜免疫保护的相关性。