Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes
Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes
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DOI：
10.1128/jvi.02073-08
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发表时间：
2009-04-01
影响因子：
5.4
通讯作者：
Walker, Bruce D.
中科院分区：
文献类型：
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作者：
Chen, Huabiao;Piechocka-Trocha, Alicja;Walker, Bruce D.
确定CD8T细胞的抗病毒效果对于免疫原设计很重要，但目前的大多数检测方法都不能衡量中和传染性病毒的反应能力。在这里，我们展示了人类免疫缺陷病毒(HIV)特异性细胞毒性T淋巴细胞(CTL)克隆和细胞系来自感染者并针对不同表位的能力在体外7天内在自体CD4T细胞中延缓感染病毒复制的能力差异超过1000倍，尽管如伽马干扰素(IFN-伽马)酶联免疫斑点(ELISPOT)试验所评估的类似活性。从体外刺激的外周血单个核细胞衍生的细胞系与来自同一人的环境特异性细胞株相比，持续中和HIV的效果更好，尽管在克隆水平上对病毒复制的无效抑制并不是环境特异性反应的普遍特征。Gag特异性细胞株的亲和力高于Env特异性细胞系，尽管亲和力与Gag或Env特异性细胞系抑制HIV复制的能力无关。在受保护性等位基因B*27和B*57限制的细胞系中，抑制作用最强，但即使在非B*27/B*57受试者中，靶向Gag表位的刺激也比靶向Env表位刺激产生更大的抑制作用。这些评估HIV特异性CD8 T细胞的功能病毒中和的结果表明，在体外扩增的CD8 T细胞中存在显著的表位和等位基因特异性的病毒中和差异，这一发现没有被目前在疫苗试验中使用的标准干扰素-伽马ELISPOT方法揭示，这可能对免疫原设计和候选艾滋病疫苗的测试至关重要。
Defining the antiviral efficacy of CD8 T cells is important for immunogen design, and yet most current assays do not measure the ability of responses to neutralize infectious virus. Here we show that human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) clones and cell lines derived from infected persons and targeting diverse epitopes differ by over 1,000-fold in their ability to retard infectious virus replication in autologous CD4 T cells during a 7-day period in vitro, despite comparable activity as assessed by gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay. Cell lines derived from peripheral blood mononuclear cells stimulated in vitro with peptides representing targeted Gag epitopes consistently neutralized HIV better than Env-specific lines from the same person, although ineffective inhibition of virus replication is not a universal characteristic of Env-specific responses at the clonal level. Gag-specific cell lines were of higher avidity than Env-specific lines, although avidity did not correlate with the ability of Gag- or Env-specific lines to contain HIV replication. The greatest inhibition was observed with cell lines restricted by the protective HLA alleles B*27 and B*57, but stimulation with targeted Gag epitopes resulted in greater inhibition than did stimulation with targeted Env epitopes even in non-B*27/B*57 subjects. These results assessing functional virus neutralization by HIV-specific CD8 T cells indicate that there are marked epitope- and allele-specific differences in virus neutralization by in vitro-expanded CD8 T cells, a finding not revealed by standard IFN-gamma ELISPOT assay currently in use in vaccine trials, which may be of critical importance in immunogen design and testing of candidate AIDS vaccines.