HIV DERIVED PEPTIDES AS CLASS II MHC ANTIGENS

作为 II 类 MHC 抗原的 HIV 衍生肽

• 批准号: 6107825
• 负责人: lawrence stern
• 金额: $ 22.2万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107825
• 关键词: HIV envelope protein gp120; MHC class II antigen; T lymphocyte; X ray crystallography; antiAIDS agent; drug design /synthesis /production; leukocyte activation /transformation; peptide chemical synthesis; peptide library; protein structure; structural biology; synthetic peptide; tissue /cell culture

(Adapted from the application) The broad, long-term objective of the proposed research is to provide structural information important for the development of peptide-based antigens that illicit immune responses protective against HIV infections. The information will be obtained by structural characterization of HIV peptides bound to class II MHC proteins and by structure-based combinatorial design of tight-binding synthetic peptide antigens. 1) To determine the mode of binding of "non-conforming" HIV-derived antigenic peptides. The t-cell response to HIV infection includes several immunodominant peptide epitopes that appear to violate the MHC peptide binding motifs determined by biochemical and structural studies. Determination of the three-dimensional structure of the human class II MHC protein HLA-DR1 in complex with "non-conforming" peptide epitopes from HIV will help characterize any novel features of their mode of binding. 2) To determine the structure of the complex of HLA-DR1 with the HIV env- derived antigenic peptide gp120[304-318]. Determination of the structure of HLA-DR1 complexes of serine and arginine variants of a gp120 that is a strong class II mhc-restricted T-cell antigen and is contained within the hypervariable V3-loop that is the primary target of neutralizing antibodies will help to characterize the immune response to gp120 and the viral mechanisms that evade the host response. 3) To design tight-binding peptide analogues that function as synthetic T-cell antigens with improved properties. Design efforts will focus on retaining conserved MHC-peptide main-chain interactions while varying the peptide backbone and side chains to maximize interactions between the peptide and pockets within the overall MHC peptide binding cleft. Three dimensional structures of peptide complexes will be used to guide the design of highly biased combinatorial libraries that will be screened for high affinity binding and long dissociating half-life.

（改编自应用程序）广泛的，长期的目标， 建议的研究是提供重要的结构信息， 开发基于肽的抗原， 预防艾滋病毒感染。有关资料将由 与II类MHC蛋白结合HIV肽的结构表征 通过基于结构的组合设计， 肽抗原 1)确定“不合格”艾滋病毒衍生物的结合方式 抗原肽T细胞对HIV感染的反应包括几种 免疫显性肽表位似乎违反MHC肽 通过生物化学和结构研究确定的结合基序。 人类II类MHC三维结构的测定 与来自HIV的“非一致”肽表位复合的蛋白HLA-DR 1 将有助于描述其结合模式的任何新特征。 2)为了确定HLA-DR 1与HIV包膜蛋白复合物的结构， 衍生的抗原肽gp 120 [304-318]。结构的确定 Gp 120的丝氨酸和精氨酸变体的HLA-DR 1复合物， 强II类MHC限制性T细胞抗原，并包含在 高变V3环是中和的主要目标， 抗体将有助于表征对gp 120的免疫应答， 逃避宿主反应的病毒机制 3)设计紧密结合的肽类似物， 具有改进性质的T细胞抗原。设计工作将集中在 保留保守的MHC-肽主链相互作用，同时改变 肽骨架和侧链，以最大化肽骨架和侧链之间的相互作用。 肽和口袋内的整体MHC肽结合裂缝。三 肽复合物的三维结构将用于指导 设计高度偏向的组合文库， 高亲和力结合和长解离半衰期。