Neutralizing Antibody Induction by Centralized Genes

集中式HIV-1免疫原检测方法是临床前检测探索的重要策略 to overcome克服HIV艾滋病毒- diversity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Env区域。我们最近在使用共有Env进行免疫原设计的初步概念验证研究中显示，1999年CON 6 gp 120和gp 140 Env蛋白表达野生型Env中和表位，并且能够诱导中和约30%野生型HIV-1原代分离株的抗体。为项目2中提议的工作提供坚实理由所需的第二个概念验证里程碑也已在去年实现？证明了中和抗体的共有基因诱导的迭代改进，2001年抗CON-S gp 140 CFI抗体显示出中和与CONG gp 140相同的B分离物谱，此外，显示出中和非B HIV-1主要分离物的重要子集。项目2将与项目1、3和4以及核心B和C协同作用，探索进一步增强集中的HIV-1基因和蛋白质的免疫原性的方法，使其能够诱导更具广泛反应性的中和抗HIV-1抗体。具体目标1。与2001年M组共识Env，CON-S相比，确定新M组共识和亚型共识Env的免疫原性。具体目标2。增强2001年CON-S Env的免疫原性，以诱导中和抗体。具体目标3。确定项目1和核心B新设计的集中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.