Increased efficacy of HIV-1 neutralization by antibodies at low CCR5 surface concentration
Increased efficacy of HIV-1 neutralization by antibodies at low CCR5 surface concentration
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DOI：
10.1016/j.bbrc.2006.07.163
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发表时间：
2006-09-29
影响因子：
3.1
通讯作者：
Dimitrov, Dimiter S.
中科院分区：
文献类型：
--
作者：
Choudhry, Vidita;Zhang, Mei-Yun;Dimitrov, Dimiter S.
据观察，一些抗体，包括CD4诱导的（CD4i）抗体IgG X5和gp41特异性抗体IgG 2F5，在基于外周血单个核细胞（PBMC）的检测中比在基于细胞系的检测中表现出更高的中和活性[J.M.宾利，T.韦林，B.科尔伯，M.B.兹维克，M.王，C.沙佩，G.施蒂格勒，R.库纳特，S.佐拉 - 帕兹纳，H.卡廷格，C.J.彼得罗普洛斯，D.R.伯顿，一组抗人免疫缺陷病毒I型单克隆抗体的综合跨分支中和分析，《病毒学杂志》78（2004）13232 - 13252]。有人假设，与用于中和检测的细胞系相比，CD4 T淋巴细胞表面的CCR5浓度较低可能是观察到的中和活性差异的一个促成因素。为了验证这一假设，并进一步阐明CCR5浓度差异对抗体中和活性的影响，我们在基于假病毒的检测中使用了一组具有明确且不同的CCR5和CD4表面浓度的海拉（HeLa）细胞系。我们观察到，CCR5细胞表面浓度而非CD4浓度对X5和其他几种CD4i抗体（包括17b13和m9）以及gp41特异性抗体2F5和4E10的抑制活性有显著影响，但对CD4结合位点抗体（CD4bs）b12没有影响。与具有高CCR5浓度（约10⁴或更高）的细胞系相比，在具有低CCR5浓度（对应于基于PBMC检测中使用的CD4 T细胞的浓度，约为每个细胞10³）的细胞系中，50%抑制浓度（IC₅₀）降低了多达两个数量级。我们的结果表明，CCR5细胞表面浓度可能是一些抗体在基于PBMC的检测中具有高中和活性的一个促成因素，但其他因素也可能起重要作用。这些发现可能对基于X5和其他CD4i抗体表位的疫苗免疫原的开发、对抗体中和HIV - 1机制的阐明以及对新型治疗方法的设计具有影响。由爱思唯尔公司出版。
It has been observed that some antibodies, including the CD4-induced (CD4i) antibody IgG X5 and the gp41-specific antibody IgG 2F5. exhibit higher neutralizing activity in PBMC-based assays than in cell line based assays [J.M. Binley, T. Wrin, B. Korber, M.B. Zwick, M. Wang, C. Chappey, G. Stiegler, R. Kunert, S. Zolla-Pazner, H. Katinger, C.J. Petropoulos, D.R. Burton, Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type I monoclonal antibodies, J. Virol. 78 (2004) 13232-13252]. It has been hypothesized that the lower CCR5 concentration on the surface of the CD4 T lymphocytes compared to that on cell lines used for the neutralization assays could be a contributing factor to the observed differences in neutralizing activity. To test this hypothesis and to further elucidate the contribution of CCR5 concentration differences on antibody neutralizing activity, we used a panel of HeLa cell lines with well-defined and differential surface concentrations of CCR5 and CD4 in a pseudovirus-based assay. We observed that the CCR5 cell surface concentration but not the CD4 concentration had a significant effect on the inhibitory activity of X5 and several other CD4i antibodies including 1713 and m9, as well as that of the gp41-specifc antibodies 2F5 and 4E10 but not on that of the CD4 binding site antibody (CD4bs), b12. The 50% inhibitory concentration (IC50) decreased up to two orders of magnitude in cell lines with low CCR5 concentration corresponding to that in CD4 T cells used in PBMC-based assays (about 10(3) per cell) compared to cell lines with high CCR5 concentration (about 10(4) or more). Our results suggest that the CCR5 cell surface concentration could be a contributing factor to the high neutralizing activities of some antibodies in PBMC-based-assays but other factors could also play an important role. These findings could have implications for development of vaccine immunogens based on the epitopes of X5 and other CD4i antibodies, for elucidation of the mechanisms of HIV-1 neutralization by antibodies, and for design of novel therapeutic approaches. Published by Elsevier Inc.