Effects of glycan modification on receptor binding site & immunogen of HIV-1 Env

抗人不同分离株中和抗体免疫原的设计 在艾滋病疫苗研究中，免疫缺陷病毒(HIV)仍然是一个未实现的目标。多个因素可能 造成了广泛产生抗艾滋病毒NtAb的困难。其中包括构象掩蔽 受体和辅受体结合位点(B)周围的保守表位，以及被多糖封闭 部分(“葡聚糖屏蔽”)。我们最近证明了C-末端N-连接的糖链的去除 HIV-1gp120的V2环的茎导致对CD4b抗体的中和敏感性增加， 突变型env介导CD4非依赖性感染的能力。用该突变型env免疫导致 在猕猴的交叉反应NtAb反应中。基于这些发现，我们假设：(1)改变 由特定的多糖修饰产生的结果导致保守表位的稳定性或可获得性增加 在受体/辅助受体b中；(2)这些保守位置的更易获得增强了它们的功能 交叉反应NtAb反应的靶点。在这个项目中，我们建议通过以下方式来检验这些假设 研究特定的糖链修饰、受体/辅助受体结合特性和 修饰的Env诱导交叉反应的NtAb和抗SHIV攻击的能力 猕猴。 具体目标： 1.确定特定的N-连接糖链修饰对环境抗原性、功能完整性、 受体/辅受体的使用和免疫原性 2.比较嗜巨噬细胞R5病毒天然和修饰包膜蛋白的免疫原性。 表现出对CD4的不同亲和力和对CD4b抗体的敏感性(来自项目1) 3.检查多糖修饰对一组显示出增强的诱导能力的环境的影响 交叉反应NtAb反应(来自项目2) 4.检测改良Env免疫原对猕猴攻击模型的保护作用 这些研究的结果可能为免疫原的设计提供进一步的见解 诱导针对HIV-1不同分离株的NtAb。 相关性(请参阅说明)：

Design of immunogens capable of inducing neutralizing antibodies (NtAb) against diverse isolates of human immunodeficiency virus (HIV) remains an unmet goal in AIDS vaccines research. Multiple factors may contribute to the difficulty in generating broadly NtAb against HIV. These include conformational masking of the conserved epitopes around the receptor and coreceptor binding sites (bs), as well as occlusion by glycan moieties ("glycan shield"). We recently demonstrated that removal of an N-linked glycan in the C-terminal stem of the V2 loop of HIV-1 gp120 resulted in increased neutralizing sensitivity to CD4bs antibodies and the ability of the mutant Env to mediate CD4-independent infection. Immunization with this mutant Env resulted in cross-reactive NtAb responses in macaques. Based on these findings, we hypothesize that: (1) changes resulting from specific glycan modifications lead to increased stability or accessibility of conserved epitopes in the receptor/coreceptor bs; (2) greater accessibility of these conserved sites enhances their function as targets for cross-reactive NtAb responses. In this project, we propose to test these hypotheses by examining the correlation between specific glycan modifications, receptor/coreceptor binding properties and the ability of the modified Env to induce cross-reactive NtAb and to project against SHIV challenge in macaques. Specific Aims: 1. To determine the effect of specific N-linked glycan modifications on Env antigenicity, functional integrity, receptor/coreceptor usage, and immunogenity 2. To compare the immunogenicity of native and modified Env from macrophage-tropic R5 viruses that exhibit differential affinity for CD4 and sensitivity to CD4bs antibodies (from Project 1) 3. To examine the effect of glycan modifications on a panel of Env that show enhanced ability to induce cross-reactive NtAb responses (from Project 2) 4. To examine the protective efficacy of modified Env immunogens in macaque challenge models Results from these studies are likely to provide further insight for the design of immunogens capable of eliciting NtAb against diverse isolates of HIV-1. RELEVANCE (Seeinstructions):