Bardhi Ariola, Wu Yanling, Chen Weizao, Li Wei, Zhu Zhongyu, Zheng Jian Hua, Wong Hing, Jeng Emily, Jones Jennifer, Ochsenbauer Christina, Kappes John C, Dimitrov Dimiter S, Ying Tianlei, Goldstein Harris
Departments of Microbiology and Immunology and Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China.
J Virol. 2017 Sep 27;91(20). doi: 10.1128/JVI.00937-17. Print 2017 Oct 15.
Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited HIV-1 and SHIV infection in humanized mouse and macaque models, respectively, including neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir.
与受感染细胞表达的人类免疫缺陷病毒1型（HIV-1）包膜蛋白结合的抗体可激发抗体依赖性细胞毒性作用（ADCC），以清除被HIV-1感染的细胞，从而抑制HIV-1感染并延缓疾病进展。用潜伏期激活剂治疗HIV-1感染者以减少其潜伏的HIV-1储存库的研究表明，他们的HIV-1特异性免疫反应不足以有效清除重新激活的潜伏HIV-1感染的T细胞。激发ADCC作用可能有助于清除重新激活的潜伏HIV-1感染细胞，以耗尽HIV-1储存库，并有助于实现功能性治愈HIV-1。用于控制和根除HIV-1感染的最有效抗体可能具有双重能力，即有效中和多种HIV-1毒株，并有效激发HIV-1特异性ADCC以清除被HIV-1感染的细胞。为此，我们构建了LSEVh-LS-F，这是一种对CD4和共受体gp120结合位点均具有特异性的广泛中和、去岩藻糖基化的六价融合蛋白。LSEVh-LS-F分别在人源化小鼠和猕猴模型中有效抑制HIV-1和猿猴-人类免疫缺陷病毒（SHIV）感染，包括中和对广泛中和抗体VRC01和3BNC117耐药的HIV-1毒株。我们开发了一种新型人源化小鼠模型，以评估人NK细胞通过ADCC介导清除被HIV-1感染细胞的作用，并利用该模型证明LSEVh-LS-F在给药后1天可迅速激发NK细胞以清除>80%的被HIV-1感染的细胞。LSEVh-LS-F通过ADCC清除被HIV-1感染细胞的能力及其广泛的中和活性支持其作为免疫治疗剂用于清除重新激活的潜伏细胞和耗尽HIV-1储存库的潜在用途。激发抗体依赖性细胞毒性作用（ADCC）以清除重新激活的潜伏HIV-1感染细胞是一种可能有助于耗尽HIV-1储存库并实现功能性治愈HIV-1的策略。为了更有效地激发ADCC，我们设计并构建了LSEVh-LS-F，这是一种对CD4和共受体gp120结合位点均具有特异性的广泛中和、去岩藻糖基化的六价融合蛋白。LSEVh-LS-F分别在人源化小鼠和猕猴模型中有效抑制HIV-1和SHIV感染，包括中和对广泛中和抗体VRC01和3BNC117耐药的HIV-1毒株。使用新型人源化小鼠模型，我们证明LSEVh-LS-F在给药后1天可迅速激发NK细胞以清除>80%的被HIV-1感染的细胞。LSEVh-LS-F通过ADCC清除被HIV-1感染细胞的能力及其广泛的中和活性支持其作为免疫治疗剂用于清除重新激活的潜伏细胞和耗尽HIV-1储存库的潜在用途。
