中国人群HLA-A11限制的HIV-1表位特异性CD8+T细胞应答免疫保护功能研究

There is a group of HIV-1 infected population known as long-term nonprogressors (LTNP). It has been shown that several special HLA class I alleles were correlated with this kind of nonprogression of disease. Most previous studies focused on the immune protection mechanism of HLA class I alleles, such as HLA-B57 and B27. It has been demonstrated that epitope specific CD8+T cells restricted by HLA-B57 or B27 showed some special characters, including resisting negative regulation, keeping normal capacity of proliferation and suppressing virus replication. It was worth note that these great characters were epitope-specific. However, These HLA class I alleles, such as HLA-B57 and -B27, are seldom taken in Asian population. HIV-1 infected individuals in China can not benefit directly from those results as mentioned above. According to these conclusions, we plan to choose HLA-A11 as study subject, which is one of the most expressed HLA class I allele in Asian population and has been demonstrated to be also associated with delayed disease progression after HIV-1 infection.11 optimal HLA-A11 restricted CD8+T cell epitopes, including the one our team identified, will be taken into account. We will evaluate the characters of these selected-epitope-specific CD8+T cells, including the ability to secret different kinds of cytokines and resist negative regulation, capacity of proliferation and suppressing virus replication, in HIV-1 infected individuals expressing HLA-A11. We try to uncover the difference to induce CD8+T cell responses among different HLA-A11-restricted epitopes and identify the one/ones with ability of immune protection. This work will supply important theoretical basis to develop next generation of HIV-1 vaccine based on T cell.

研究显示一些HLA-I类等位基因与HIV-1感染疾病缓慢进展相关。以往研究多集中在HLA-B57、B27等等位基因，发现此类等位基因限制的CTL具有抵抗负性调节、保持良好增殖能力、持续抑制病毒复制等特征，且具有表位特异性。然而，上述等位基因在亚洲人群所占比例极少，前述研究成果不能使广大中国HIV-1感染者受益。据此，本研究拟选取与HIV-1疾病缓慢进展相关且在亚洲人群分布广泛的HLA-A11等位基因为研究对象，以HLA-A11限制的最优表位为候选表位，入组HIV-1感染者，采集外周血单个核细胞，利用酶联免疫斑点吸附试验、流式细胞术、细胞增殖试验、病毒抑制试验等手段对HLA-A11限制的表位特异性CD8+T细胞抵抗负性调节能力、增殖能力及对病毒复制的抑制能力等方面进行评估。评价表位间差异，筛选具有免疫保护功能的优势表位。为下一代以T细胞表位为基础的HIV-1候选疫苗研发提供重要的理论依据。

研究表明HLA-A11与HIV-1感染后疾病缓慢进展有关。但是这一现象背后的机制至今不明。本研究试图通过评价HLA-A1101限制的HIV-1表位特异性CD8+T细胞应答揭示这一机制。本研究入组15例携带HLA-A1101等位基因的HIV-1感染者，其中长期无进展者5例，慢性进展者10例。我们比较了两组间HLA-A1101限制的表位特异性CD8+T细胞数量、分泌细胞因子、增殖能力和病毒抑制能力，并对表位特异性CD8+T细胞表面PD-1及Tim-3的表达水平进行的检测。结果显示两组人群中HLA-A1101限制的表位特异性CD8+T细胞数量及功能均没有显著差异。携带HLA-A1101等位基因的HIV-1感染长期无进展者体内HLA-A1101限制的表位特异性CD8+T细胞未表现出与携带HLA-B5701等位基因的HIV-1感染长期无进展者体内HLA-B5701限制的表位特异性CD8+T细胞相当的免疫保护功能。基于本研究目前所得结果，HLA-A1101限制的CD8+T细胞应答可能不是携带HLA-A1101等位基因HIV-1感染者疾病缓慢进展的主要原因。