HIV DERIVED PEPTIDES AS CLASS II MHC ANTIGENS

(改编自申请) 拟议的研究将提供对 非法免疫反应多肽类抗原的研究进展 预防艾滋病毒感染。这些信息将通过以下方式获得 HIV与第II类MHC蛋白结合多肽的结构特征 并通过基于结构的紧束缚合成的组合设计 多肽抗原。 1)确定“不符合”的HIV来源的结合方式 抗原肽。T细胞对艾滋病毒感染的反应包括几个方面 似乎违反MHC多肽的免疫优势多肽表位 由生化和结构研究确定的结合基序。 人类第II类MHC三维结构的测定 人类免疫缺陷病毒“非一致性”表位复合体中的蛋白质HLA-DR1 将有助于描述其绑定模式的任何新特征。 2)确定人类白细胞抗原-DR1与人类免疫缺陷病毒包膜的复合体的结构。 衍生抗原肽gp120[304-318]。结构的确定 Gp120的丝氨酸和精氨酸变体的人类白细胞抗原-DR1复合体 强的II类MHC限制性T细胞抗原，包含在 高变量V3循环，它是中和的主要目标 抗体有助于表征对gp120和gp120的免疫反应。 逃避宿主反应的病毒机制。 3)设计具有合成功能的紧密结合的多肽类似物 具有改进特性的T细胞抗原。设计工作将重点放在 保留保守的MHC-多肽主链相互作用，同时改变 多肽主链和侧链，以最大化之间的相互作用 多肽与口袋内的整体MHC多肽结合缝隙。三 多肽复合体的空间结构将被用来指导 设计要筛选的高度偏向的组合库 高亲和力结合，解离半衰期长。

(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.