Neutralizing Antibody Induction by Centralized Genes

集中式HIV-1免疫原法是探索临床前检测的重要策略 以克服艾滋病毒的多样性。为了诱导中和抗体，集中的基因应该 捕获对病毒感染性重要的保守的Env区域。我们最近在使用一致的env用于免疫原设计的初步概念验证研究中表明，1999年CON6 gp120和gp140 env蛋白表达了野生型env中和表位，并能够诱导出抗体，中和了约30%的野生型HIV-1初级分离株。项目2中提出的工作的坚实理论基础所需的第二个概念证明里程碑也在去年实现了-证明了中和抗体的共识基因诱导的迭代改进，2001年抗CON-S gp140CFI抗体被证明中和了与Cong gp140相同的B分离株谱，此外，还被证明中和了一组重要的非B型艾滋病毒-1初级分离株。项目2将与项目1、3和4以及核心B和C协同工作，探索如何进一步提高集中的艾滋病毒-1基因和蛋白的免疫原性，使其能够诱导更广泛的反应性中和抗艾滋病毒-1抗体。具体目的1.确定新的M群一致性和亚型一致性Env与2001年M组一致性Env、Con-S的免疫原性。具体目的2.提高2001年S冠状病毒的免疫原性，以诱导中和抗体。具体目的3.确定新设计的项目1和核心B的集中式Env的抗原性和免疫原性。

Centralized HIV-1 immunogen approach is an important strategy to explore for preclinical testing to overcome HIV- diversity. For induction of neutralizing antibodies, centralized genes should capture the conserved Env regions that are important for virus infectivity. We have recently shown in initial proof of concept studies for use of consensus Envs for immunogen design, that year 1999 CON6 gp120 and gp140 Env proteins expressed wildtype Env neutralizing epitopes, and were able to induce antibodies that neutralized about 30% of wild-type HIV-1 primary isolates. The second proof of concept milestone needed for a firm rationale for the work proposed in Project 2 has also been achieved within the last year?that of demonstration of iterative improvement of consensus gene induction of neutralizing antibodies, with year 2001 anti-CON-S gp140CFI antibodies shown to neutralize the same spectrum of B isolates as CONG gp140, and, in addition, shown to neutralize a significant subset of non-B HIV-1 primary isolates. Project 2 will synergize with Projects 1, 3 and 4 and Cores B and C by exploring ways to further enhance the immunogenicity of centralized HIV-1 genes and proteins for their ability to induce more broadly reactive neutralizing anti-HIV-1 antibodies. Specific Aim 1. To determine the immunogenicity of newer group M consensus and subtype consensus Envs compared to Year 2001 group M consensus Env, CON-S. Specific Aim 2. To enhance the immunogenicity of Year 2001 CON-S Env for induction of neutralizing antibodies. Specific Aim 3. To determine the antigenicity and immunogenicity of newly designed centralized Envs from Project 1 and Core B.