A Novel HIV-1 Vaccine Targeting the 12 protease Cleavage Sites

一种针对 12 个蛋白酶切割位点的新型 HIV-1 疫苗

• 批准号: 9283446
• 负责人: Ma Luo
• 金额: $ 71.26万
• 依托单位: UNIVERSITY OF MANITOBA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-13 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283446
• 关键词: AIDS/HIV problem; Amino Acids; Antigenic Diversity; Antigens; Aspartic Acid; Attenuated; CD4 Positive T Lymphocytes; Cell Maintenance; Cells; Data; Dendritic Cells; Development; Disadvantaged; Dose; Enzymes; Exhibits; Experimental Models; Generations; HIV; HIV Antigens; HIV Protease; HIV Vaccine Trials Network; HIV resistance; HIV vaccine; HIV-1; HIV-1 vaccine; Immune response; Immune system; Immunologics; Impairment; Individual; Infection; Inflammatory Response; Investigation; Learning; Length; Macaca; Mediating; Modality; Modeling; Molecular; Mutate; Mutation; Nanostructures; Natural Immunity; Pathogenicity; Peptide Hydrolases; Peptides; Pilot Projects; Polyproteins; Population; Predisposition; Preventive vaccine; Process; Production; Reaction; Recombinants; SIV; Site; Smallpox Vaccine; System; Testing; Vaccines; Vagina; Vesicular stomatitis Indiana virus; Viral; Viral Load result; Viremia; Virion; Virus; base; cohort; female sex worker; fitness; immune activation; innovation; nonhuman primate; novel; novel strategies; particle; prevent; prophylactic; protective efficacy; public health relevance; response; secondary outcome; sex; sobriety; vaccine candidate; vaccine development; vaccine efficacy; vector; viral fitness; virology

DESCRIPTION (provided by applicant): Developing an effective preventative vaccine for HIV-1 has proved to be an enormous challenge. The classical vaccine approach has failed thus far or produced modest efficacy in dealing with a virus infects a key component of immune system and exhibits great antigenic diversity and mutates rapidly. Novel approaches and ideas are needed to develop a preventative vaccine to HIV-1. Edward Jenner developed the successful smallpox vaccine based on the natural immunity observed in milkmaids. Thus, the correlates of natural immunity to HIV-1 documented in highly exposed uninfected individuals may provide a vital clue for the development of a preventative vaccine to HIV-1. Learning from immunologic correlates of protection from HIV-1 infection in a group of highly exposed HIV resistant Nairobi female sex workers, we propose that an effective preventative vaccine to HIV-1 should target key sites of HIV-1 and a vaccine targeting the 12 protease cleavage sites of HIV-1 can prevent HIV-1 acquisition. HIV protease is a small 99-amino acid aspartic enzyme that mediates the cleavage of Gag, Gag-Pol and Nef precursor polyproteins. The process is highly specific, temporally regulated and essential for the production of infectious viral particles. A total of twelve proteolytic reactions are required to generate an infectious virion. Therefore, a vaccine generating immune responses to the 12 protease cleavage sites of HIV-1 would have several major advantages. First, the host immune response could destroy the virus before its permanent establishment in the host. Second, the vaccine could force the virus to accumulate mutations eliminating the normal function of the HIV protease thus eliminating infectious virions. Third, restricting the immune responses to these sites can avoid distracting immune responses that often generate unwanted inflammatory responses, excess immune activation, and attract more targets for HIV- 1 infection, establishment and spread. To test this hypothesis we will use Mauritian Cynomolgus macaques and pathogenic SIVmac251 as an experimental model and peptides overlapping the 12 protease cleavage sites of SIVmac239 as immunogens to compare with full Gag and full Env as immunogens. We will deliver these immunogens with a) a modified vesicular stomatitis virus (VSV) vector system capable of targeting dendritic cells and generating robust immune responses; b) a nanostructure mucosal delivery system. The protection from infection will be examined by the ability of the macaques to resist repeated low dose intravaginal pathogenic SIVmac251 challenges. Secondary outcome such as viral load set point and CD4+ T cell decline will also be compared. Viral fitness analysis will be conducted to validate that the focused immune responses can drive deleterious viral mutation and produce virus of attenuated fitness and transmissibility. Confirmation of this hypothesis and vaccine approach will shift the paradigm of HIV vaccine development and develop an effective preventative HIV vaccine.

描述（由申请人提供）：开发有效的HIV-1预防性疫苗已被证明是一个巨大的挑战。经典的疫苗方法迄今为止在处理病毒感染免疫系统的关键组成部分并表现出巨大的抗原多样性和快速突变方面失败或产生适度的功效。开发HIV-1预防性疫苗需要新的方法和想法。爱德华詹纳根据在挤奶女工身上观察到的天然免疫力成功地研制出天花疫苗。因此，在高度暴露的未感染个体中记录的对HIV-1的天然免疫的相关性可能为开发HIV-1的预防性疫苗提供重要线索。从一组高度暴露的HIV耐药内罗毕女性性工作者中保护HIV-1感染的免疫学相关性中学习，我们建议有效的HIV-1预防性疫苗应该靶向HIV-1的关键位点，靶向HIV-1的12个蛋白酶切割位点的疫苗可以预防HIV-1的获得。HIV蛋白酶是一种小的99个氨基酸的天冬氨酸酶，介导Gag、Gag-Pol和Nef前体多蛋白的切割。该过程是高度特异性的，时间调节的，并且对于感染性病毒颗粒的产生是必需的。总共需要十二个蛋白水解反应来产生感染性病毒体。因此，对HIV-1的12个蛋白酶切割位点产生免疫反应的疫苗将具有几个主要优势。首先，宿主的免疫反应可以在病毒在宿主中永久建立之前将其摧毁。其次，疫苗可以迫使病毒积累突变，消除HIV蛋白酶的正常功能，从而消除感染性病毒粒子。第三，将免疫反应限制在这些部位可以避免分散免疫反应，这些免疫反应通常会产生不必要的炎症反应，过度的免疫激活，并吸引更多的HIV- 1感染，建立和传播的目标。为了检验这一假设，我们将使用印度尼西亚食蟹猴和致病性SIVmac 251作为实验模型，并将与SIVmac 239的12个蛋白酶切割位点重叠的肽作为免疫原，以与作为免疫原的全Gag和全Env进行比较。我们将用a）能够靶向树突状细胞并产生强大免疫应答的经修饰的水泡性口炎病毒（VSV）载体系统; B）纳米结构粘膜递送系统递送这些免疫原。将通过猕猴抵抗反复低剂量阴道内致病性SIVmac 251攻击的能力来检查对感染的保护。还将比较次要结局，如病毒载量设定点和CD 4 + T细胞下降。将进行病毒适应度分析，以验证集中的免疫应答可驱动有害病毒突变并产生适应度和传播性减弱的病毒。这一假设和疫苗方法的证实将改变艾滋病毒疫苗开发的范式，并开发出有效的预防性艾滋病毒疫苗。

项目成果

Modulating the immune system through nanotechnology.

通过纳米技术调节免疫系统。

• DOI: 10.1016/j.smim.2017.09.007
• 发表时间: 2017-12
• 期刊: Seminars in immunology
• 影响因子: 7.8
• 作者: Dacoba TG;Olivera A;Torres D;Crecente-Campo J;Alonso MJ
• 通讯作者: Alonso MJ

Natural and cross-inducible anti-SIV antibodies in Mauritian cynomolgus macaques.

• DOI: 10.1371/journal.pone.0186079
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Li H;Nykoluk M;Li L;Liu LR;Omange RW;Soule G;Schroeder LT;Toledo N;Kashem MA;Correia-Pinto JF;Liang B;Schultz-Darken N;Alonso MJ;Whitney JB;Plummer FA;Luo M
• 通讯作者: Luo M

A novel HIV vaccine targeting the protease cleavage sites.

• DOI: 10.1186/s12981-017-0174-7
• 发表时间: 2017-09-12
• 期刊: AIDS research and therapy
• 影响因子: 2.2
• 作者: Li H;Omange RW;Plummer FA;Luo M
• 通讯作者: Luo M