恒河猴Mamu-B*08和B*03呈递免疫缺陷病毒抗原表位的分子机制

Human elite controllers (EC) are a rare population of individuals that control HIV replication to extremely low levels without medical intervention. Similarly, a small number of macaques control pathogenic SIV replication and become EC. These unique animals are a valuable resource to complement human studies in understanding immunodeficiency virus pathogenesis and immunity. The human ECs are long-term nonprogressors,and resistance is associated with the presence of particular HLA-B*27 molecules. In a similar fashion, 50% of Mamu-B*08-positive Indian rhesus macaques control SIVmac239 replication and become elite controllers with chronic-phase viremia <1000 viral RNA copies/ml. Interestingly, despite substantial sequence differences among Mamu-B*08/B*03 and HLA-B*2705, the peptide-binding repertoires of these three MHC class I molecules share a remarkable degree of overlap, suggesting that the nature of the peptide bound by the MHC class I molecule may play an important role in control of immunodeficiency virus replication. ..In this study, we will resolve the crystal structures of Mamu-B*08 and B*03 in complex with different peptides corresponding to immunodominant SIVmac239-derived CD8(+) T cell epitopes. The findings will provide novel insights into the structural basis of diverse peptide presented by Mamu-B*08 and B*03, which informs our understanding of the association between Mamu-B*08 /B*03 and the control of SIV replication.

携带猴免疫缺陷病毒（Simian Immunodeficiency Virus，SIV )的恒河猴是研究人类免疫缺陷病毒（human immunodeficiency virus，HIV）感染的最理想动物模型。未进行任何抗病毒治疗的情况下，"精英控制者"（Elite controller, 简称EC）感染免疫缺陷病毒可以自发地、持续性地控制病毒复制或疾病进展。已有研究发现人类EC群体中HLA-B*27阳性率较高。而Mamu-B*08和B*03与HLA-B*27基因序列相似，识别的多肽序列也相似。且Mamu-B*08在恒河猴EC群体中比例较高，可以使慢性感染期的SIV滴度降低，可能是研究人类EC的很好模型。本项目旨在通过解析Mamu-B*08和B*03与SIV抗原表位的复合物结构，揭示宿主抑制艾滋病毒以及病毒逃逸的免疫机理，从而为艾滋疫苗的研发提供新的方向。

携带猴免疫缺陷病毒（SIV )的恒河猴是研究人类免疫缺陷病毒（HIV）感染的最理想动物模型。未进行任何抗病毒治疗的情况下，“精英控制者”（Elite controller, 简称EC）感染免疫缺陷病毒可以自发地、持续性地控制病毒复制或疾病进展。已有研究发现人类EC 群体中HLA-B*27阳性率较高。而Mamu-B*08 和B*03 与HLA-B*27 基因序列相似，识别的多肽序列也相似。且Mamu-B*08 在恒河猴EC 群体中比例较高，可以使慢性感染期的SIV 滴度降低，可能是研究人类EC 的很好模型。..课题组成功获得了多肽-恒河猴MHC-I的复合物蛋白。经过分子筛纯化，晶体筛选和优化，得到了复合物的晶体。通过X-射线衍射收集数据，利用分子置换法解析获得了Mamu-B*08和 Nef RL10的复合物三维结构。 Mamu-B*08/RL10复合物晶体最高分辨率为1.9Å，属于I4空间群，晶胞参数为a=148.61 Å，b=148.61Å，c=57.23 Å，α=β=γ=90°，每个不对称单元中含有1个分子。..Nef RL10与Mamu-B*08的复合物结构与经典的多肽-MHC-I复合物结构相似。Nef RL10和Vif RL9的主要锚定残基都是第二位的精氨酸和最后一位的亮氨酸。RL10的N-端P1、P2和P4位的精氨酸残基均与Mamu-B*08重链的氨基酸残基通过氢键形成盐桥，P1位也起到了重要的锚定残基的作用。Nef RL10和Vif RL9的P2位不仅通过精氨酸的大侧链被深深包埋在B口袋中，并且Mamu-B*08主链上的第66位精氨酸（Arg66）和第163位苏氨酸（Thr163）通过范德华力和水分子形成了一个牢固的桥，紧紧包裹住P2。这些独特的结构极大地增强了多肽和Mamu-B*08的亲和力。..总之，本研究成功解析了恒河猴Mamu-B*08和 SIV Nef RL10的复合物结构，揭示了Mamu-B*08呈递SIV抗原表位的分子机制，阐明了Mamu-B*08与其抗原表位（如Nef RL10）通过独特的方式进行紧密结合，大大增强了Mamu-B*08识别和呈递SIV抗原表位的几率，从而在免疫缺陷病毒感染过程中的起到了免疫保护作用。