摘要
目的检测靶向近膜区（membrane proximal external region，MPER）中和抗体2F5、4E10对HIV逃逸N肽抑制剂的突变株（简称逃逸突变株）的中和效果，分析逃逸突变对2F5和4E10中和效果的影响，探讨中和抗体2F5、4E10与N肽抑制剂联合使用治疗艾滋病（acquired immunodeficiency syndrome，AIDS）的可能性。方法选取前期工作获得的HIV逃逸N肽抑制剂N36和IZN36的突变株包膜，构建含有这些逃逸突变的HIV包膜假病毒，利用假病毒感染实验测定感染靶细胞能力；中和实验检测2F5、4E10对突变株的中和效果；分子构象模拟分析逃逸突变影响sCD4和中和抗体中和效果的分子机制。结果在所检测的突变中，对HR2区逃逸突变株，2F5的中和效果较野生型弱，sCD4的中和效果与野生型相似，并且除E648K突变株外，4E10对其余HR2区逃逸突变株的中和效果较野生型弱；而2F5和sCD4对HR1区逃逸突变株的中和效果增强，尤其是对含有两个突变的包膜假病毒的中和效果显著增强。结论2F5与sCD4对逃逸突变株的中和效果呈正相关。2F5对HR1区逃逸突变株的中和效果增强，为2F5与N肽抑制剂联合应用治疗艾滋病提供可能。
ObjectiveTo explore the possibility of combined usage of the N-peptide inhibitors with the neutralizing antibodies, 2F5 and 4E10, targeting membrane proximal external region （MPER） of viral envelopefor the treatment of acquired immunodeficiency syndrome（AIDS）.MethodsThe HIVmutants, N36 and IZN36, which escapedfrom the N peptide inhibitors, were screened in our previous study.The pseudoviruses containing theseescape mutations were constructed and heirinfectivitywasdetected.The neutralization effects of 2F5 and 4E10 on the escape mutants were determined byneutralization assays.Molecular modeling was used to analyze the molecular mechanisms of the neutralization effectsof the neutralizing antibodiesof sCD4.ResultsAmong the tested mutants, the neutralization effects of 2F5 on the mutants containing HR2 mutationswere reducedcomparingwith wild type.The neutralization effects of sCD4 were similar to those of wild type.Meanwhile, the neutralization effects of 4E10on the mutants containing HR2 mutations were weakenedexcept E648K.However, the neutralization effects of 2F5 and sCD4 on escape mutants containing HR1 mutation（s） were enhanced, especially the mutants containing two mutations in the envelope.ConclusionThe neutralization effects of 2F5 on the HIV mutantsescapedfromN-peptide inhibitorswere positively correlated with those of sCD4.The neutralization effects of 2F5 on the escape mutantscontaining HR1 mutation（s） were enhanced.These results indicate that it might be possible to combineN-peptide inhibitors with 2F5 for the treatment of AIDS.
作者
原晨
张雪莹
魏相辉
凌虹
庄敏
Yuan Chen, Zhang Xueying, Wei Xianghui, Ling Hong, Zhuang Min(Department of Microbiology, Harbin Medical University, Wu Lien-Teh Institute, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Infection and Immunity;Key Laboratory of Pathogen Biology in Heilongjiang Provincial Education Institute ,Harbin 150081, Chin)
出处
《国际免疫学杂志》
CAS
2018年第2期129-134,共6页
International Journal of Immunology
基金
国家自然科学基金（81201321）
第46批教育部留学归国人员科研启动基金
关键词
人类免疫缺陷病毒
包膜
N肽抑制剂
逃逸突变
中和抗体
Human immunodeficiency virus
Envelope
N-peptide inhibitors
Escape mutations
Neutralizing antibody
