Novel SIVsmm strains for analysis of mucosal transmission and vaccine protection

用于分析粘膜传播和疫苗保护的新型 SIVsmm 毒株

• 批准号: 8695280
• 负责人: GEORGE M SHAW
• 金额: $ 251.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695280
• 关键词: Alabama; Antibodies; Area; Cercocebus atys; Cervical; Clinical; Clinical Trials; Cloning; Event; Failure; Genetic; Genome; HIV-1; HIV/SIV vaccine; Human; Infection; Infection prevention; Knowledge; Lead; Macaca mulatta; Modeling; Molecular Analysis; Molecular Cloning; Mucosal Immune Responses; Mucous Membrane; Nature; Pathogenicity; Research; Research Personnel; SIV; T-Lymphocyte; Testing; Universities; Vaccine Design; Vaccine Research; Vaccines; Vagina; Viral; Virus; base; efficacy trial; in vivo; insight; novel; pandemic disease; rectal; transmission process; vaccine development; vaccine evaluation; virus host interaction

The expanding HIV-1 pandemic, and the failure of human efficacy trials of T-cell and antibody-based vaccines, highlight the major gaps in knowledge that must be filled in order to pursue rational HIV-1 vaccine design and development. One of the most important knowiedge gaps relates to the precise nature of early virus-host interactions that lead to virus transmission and productive clinical infection. This application is a new HIVRAD proposal by investigators whose recent scientific discoveries relate directly to this priority area of research. These discoveries - the identification of transmitted/founder HIV-1 and SIV genomes (Keele 2008; Keele 2009; Salazar 2009), the identification of genetically-divergent SIVsmm strains in naturallyinfected sooty mangabeys (Apetrei 2005; Apetrei 2007), and the identification of innate mucosal immune responses modulating early virus-host interactions (Estes 2006; Estes 2008; Li 2009) - create a unique and timely opportunity to focus three cutting edge research themes on a high priority HIV/SIV vaccine research problem. The current proposal is comprised of three interrelated projects and two cores led by investigators at the University of Alabama at Birmingham (Shaw and Hahn); the University of Pittsburgh (Apetrei and Pandrea); and NCI-Frederick (Estes, Keele and Lifson). Project #1 is "Mucosal transmission and pathogenicity of novel SIVsmm virus strains (Apetrei)." Project #2 is "Identification, cloning and characterization of transmitted/founder SIVsmm (Hahn)." Project #3 is "Molecular analysis of the mucosal SIVsmm transmission bottleneck (Shaw)." Collectively, the projects will test this hypothesis: Identification, molecular cloning, and in vivo analysis of naturally-occurring mucosally-transmitted strains of SIVsmm corresponding to transmitted/founder viruses will reveal viral-host interactions responsible for selective SIV transmission across rectal, vaginal and cervical mucosa and will provide novel, genetically-divergent, pathogenic virus challenge strains for vaccine testing. A key deliverable of this research to the SIV/HIV vaccine field, in addition to new scientific insights into mucosal transmission, will be 18 molecular clones of transmitted/founder viruses representing three widely divergent SIVsmm genetic lineages for use as potential challenge stocks.

HIV-1大流行的扩展以及T细胞和基于抗体的人类功效试验的失败 疫苗，强调必须填补的主要知识差距才能追求理性的HIV-1疫苗 设计与开发。最重要的知识差距之一与早期的确切本质有关 导致病毒传播和生产性临床感染的病毒宿主相互作用。这个应用程序是 调查人员的新希夫拉德提案，最近的科学发现与此优先领域直接相关 研究。这些发现 - 传播/创始人HIV -1和SIV基因组的鉴定（Keele 2008; Keele 2009; Salazar 2009），在自然感染中遗传性差的SIVSMM菌株的鉴定 烟灰芒果（Apetrei 2005； Apetrei 2007）和先天粘膜免疫的鉴定 调节早期病毒宿主相互作用的反应（Estes 2006; Estes 2008; Li 2009） - 创建一个独特的和 及时的机会将三个尖端研究主题集中在高优先级艾滋病毒/SIV疫苗研究上 问题。当前的提议由三个相互关联的项目和两个核心组成 在伯明翰的阿拉巴马大学（肖和哈恩）；匹兹堡大学（Apetrei和 Pandrea）;和NCI-Frederick（Estes，Keele和Lifson）。项目1是“粘膜传输和 新型SIVSMM病毒菌株（Apetrei）的致病性。“项目＃2是”识别，克隆和 传播/创始人SIVSMM（HAHN）的表征。“项目＃3是”粘膜的分子分析 SIVSMM传输瓶颈（Shaw）。 分子克隆和体内分析SIVSMM的天然粘膜传播菌株 对应于传播/创始人病毒的相对应揭示导致选择性SIV的病毒宿主相互作用 跨直肠，阴道和宫颈粘膜传播，将提供新颖的，遗传性的， 致病病毒挑战菌株用于疫苗测试。这项研究向SIV/HIV的关键可交付 除了对粘膜传播的新科学见解外，疫苗场还将是18个分子克隆 传播/创始人的病毒代表三种广泛不同的SIVSMM遗传谱系作为用作 潜在的挑战股。

项目成果

Targeted Isolation of Antibodies Directed against Major Sites of SIV Env Vulnerability.

• DOI: 10.1371/journal.ppat.1005537
• 发表时间: 2016-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Mason RD;Welles HC;Adams C;Chakrabarti BK;Gorman J;Zhou T;Nguyen R;O'Dell S;Lusvarghi S;Bewley CA;Li H;Shaw GM;Sheng Z;Shapiro L;Wyatt R;Kwong PD;Mascola JR;Roederer M
• 通讯作者: Roederer M