Stabilizing HIV-1 Trimers by Linking gp120 Subunits

通过连接 gp120 亚基稳定 HIV-1 三聚体

基本信息

  • 批准号:
    8534690
  • 负责人:
  • 金额:
    $ 16.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-10 至 2014-04-30
  • 项目状态:
    已结题

项目摘要

An effective HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (nAbs) that possess a unique ability to bind to authentic Env trimers. It is logical, therefore, that these trimers may be able to elicit nAbs in a vaccine setting. In addition to trimers, however, particles bear non-functional Env that appears to dominate Ab responses and dampen or delay nAb development. We will test the hypothesis that anti-trimer responses to particulate vaccines are improved when unfettered by non-functional Env. Our Specific Aims are: Specific Aim 1: To Investigate the effect of V1V2 and V3 loop mutations on lateral trimer stability. One strategy to eliminate undesirable Ab targets on VLPs may be to laterally stabilize trimers (i.e. between adjacent gp120/gp41 protomers) by an inter-molecular disulfide bridge. To assist in the placement of cysteines, we will perform targeted alanine scanning mutagenesis of authentic Env trimers. We have preliminary evidence that screening by BN-PAGE makes the identification of laterally unstable mutants feasible. Available data suggests that variable loop interactions may stabilize neighboring gp120 subunits. Specific Aim 2: To laterally stabilize authentic trimers by introducing an inter-gp120 disulfide bond. We will make pairs of cysteine substitutions in V1V2 and V3 loops to try to introduce a disulfide bridge, termed "SOSVV", focusing on positions identified in Aim 1. To test whether a V-V disulfide bridge is present, we will evaluate trimer stability to ionic detergents and reducing agents. Native PAGE binding studies will be used to assess trimer authenticity as indicated by nAb binding exclusivity. We will also examine the ability of the SOSVV trimers to function in infection and the stability of SOSVV mutants expressed as a soluble gp140. Specific Aim 3: To evaluate the ability of unfettered authentic trimers to elicit nAbs in rabbits. If SOSVV forms stable trimers with no non-functional Env contamination, we will test their immunogenicity in rabbits. If neutralizing responses fail to develop, we will try higher doses and hyperimmunization. Another possibility would be to use VLPs complexed with IgG to augment nAb responses. Contingent immunogens will either be soluble SOSVV or VLP immunogens in which non-functional targets are masked by species-matched IgG. Results will drive successive immunizations to solve problems and amplify neutralizing responses. Specific Aim 4: To augment antibody responses to authentic trimers in macaques. The R33 phase has 3 main components. First, we will adapt our immunogens for macaques. Macaques offer both opportunities and challenges. For example, broad nAbs can be generated in SHIV-infections. However, Env-based immunogens may engage endogenous primate CD4, leading to the elicitation of non-neutralizing Ab specificities. Therefore, we will evaluate CD4 binding knockout trimers. We will immunize two groups of 12 macaques and challenge the second group with a heterologous SHIV. Second, we will try to improve nAb titer and breadth in rabbits by various strategies. Third, we will try to improve the production, purification and quality of VLPs.
一种有效的HIV-1疫苗可能需要诱导具有a

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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JAMES M BINLEY其他文献

JAMES M BINLEY的其他文献

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{{ truncateString('JAMES M BINLEY', 18)}}的其他基金

Rescue of broadly neutralizing mAbs using native trimer
使用天然三聚体拯救广泛中和的单克隆抗体
  • 批准号:
    8841172
  • 财政年份:
    2014
  • 资助金额:
    $ 16.51万
  • 项目类别:
Pure and Authentic HIV-1 Env Immunogens
纯正的 HIV-1 包膜免疫原
  • 批准号:
    8841254
  • 财政年份:
    2014
  • 资助金额:
    $ 16.51万
  • 项目类别:
Rescue of broadly neutralizing mAbs using native trimer
使用天然三聚体拯救广泛中和的单克隆抗体
  • 批准号:
    8860105
  • 财政年份:
    2014
  • 资助金额:
    $ 16.51万
  • 项目类别:
Rescue of broadly neutralizing mAbs using native trimer
使用天然三聚体拯救广泛中和的单克隆抗体
  • 批准号:
    8459997
  • 财政年份:
    2012
  • 资助金额:
    $ 16.51万
  • 项目类别:
Rescue of broadly neutralizing mAbs using native trimer
使用天然三聚体拯救广泛中和的单克隆抗体
  • 批准号:
    8411099
  • 财政年份:
    2012
  • 资助金额:
    $ 16.51万
  • 项目类别:
Pure and Authentic HIV-1 Env Immunogens
纯正的 HIV-1 包膜免疫原
  • 批准号:
    8141068
  • 财政年份:
    2011
  • 资助金额:
    $ 16.51万
  • 项目类别:
Pure and Authentic HIV-1 Env Immunogens
纯正的 HIV-1 包膜免疫原
  • 批准号:
    8427355
  • 财政年份:
    2011
  • 资助金额:
    $ 16.51万
  • 项目类别:
Inducing HIV-1 NAb Breadth by Native Trimer Prime-Boost Vaccination
通过天然三聚体初免加强疫苗接种诱导 HIV-1 NAb 广度
  • 批准号:
    10406231
  • 财政年份:
    2011
  • 资助金额:
    $ 16.51万
  • 项目类别:
Pure and Authentic HIV-1 Env Immunogens
纯正的 HIV-1 包膜免疫原
  • 批准号:
    8233322
  • 财政年份:
    2011
  • 资助金额:
    $ 16.51万
  • 项目类别:
Inducing HIV-1 NAb Breadth by Native Trimer Prime-Boost Vaccination
通过天然三聚体初免加强疫苗接种诱导 HIV-1 NAb 广度
  • 批准号:
    9269982
  • 财政年份:
    2011
  • 资助金额:
    $ 16.51万
  • 项目类别:

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