Generation of HIY-resistant cells with a single-domain antibody:implications for HIV-1 gene therapy  

作　　者：Hongliang Jin Xiaoran Tang Li Li Yue Chen Yuanmei Zhu Huihui Chong and Yuxian He 

机构地区：[1]NHC Key Laboratory of Systems Biology of Pathogen Institute of Pathogen Biology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [2]Center for AIDS Research,Chinese Academy of Medical Sciences and Peking Union Medical Colley,Beijing,China

出　　处：《Cellular & Molecular Immunology》2021年第3期660-674,共15页中国免疫学杂志（英文版）

基　　金：supported by grants from the CAMS Innovation Fund for Medical Sciences(2017-I2M-1-014);National Science and Technology Major Project of China(2018ZX10301103 and 2017ZX10202102-001-003);National Natural Science Foundation of China(81630061).

摘　　要：The cure or functional cure of the"Berlin patient"and"London patient"indicates that infusion of HIV-resistant cells could be a viable treatment strategy.Very recently,we genetically linked a short-peptide fusion inhibitor with a glycosylphosphatidylinositol(GPI)attachment signal,rendering modified cells fully resistant to HIV infection.In this study,GPI-anchored m36.4,a single-domain antibody(nanobody)targeting the coreceptor-binding site of gp120,was constructed with a lentiviral vector.We verified that m36.4 was efficiently expressed on the plasma membrane of transduced TZM-bl cells and targeted lipid raft sites without affecting the expression of HIV receptors(CD4,CCR5,and CXCR4).Significantly,TZM-bl cells expressing GPI-m36.4 were highly resistant to infection with divergent HIV-1 subtypes and potently blocked HIV-1 envelope-mediated cell-cell fusion and cell-cell viral transmission.Furthermore,we showed that GPI-m36.4-modified human CEMss-CCR5 cells were nonpermissive to both CCR5-and CXCR4-tropic HIV-1 isolates and displayed a strong survival advantage over unmodified cells.It was found that GPI-m36.4 could also Impair HIV-1 Env processing and viral infectivity in transduced cells,underlying a multifaceted mechanism of antiviral action.In conclusion,our studies characterize m36.4 as a powerful nanobody that can generate HIV-resistant cells,offering a novel gene therapy approach that can be used alone or in combination.

关 键 词：HIV-1 gene therapy resistant cell single-domain antibody GLYCOSYLPHOSPHATIDYLINOSITOL 

分 类 号：R512.91[医药卫生—内科学]