Julg Boris, Pegu Amarendra, Abbink Peter, Liu Jinyan, Brinkman Amanda, Molloy Katherine, Mojta Shanell, Chandrashekar Abishek, Callow Katherine, Wang Keyun, Chen Xuejun, Schmidt Stephen D, Huang Jinghe, Koup Richard A, Seaman Michael S, Keele Brandon F, Mascola John R, Connors Mark, Barouch Dan H
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
J Virol. 2017 Jul 27;91(16). doi: 10.1128/JVI.00498-17. Print 2017 Aug 15.
Passive immunotherapy against HIV-1 will most likely require broadly neutralizing antibodies (bnAbs) with maximum breadth and potency to ensure therapeutic efficacy. Recently, the novel CD4 binding site antibody N6 demonstrated extraordinary neutralization breadth and potency against large panels of cross-clade pseudoviruses. We evaluated the antiviral activity of N6-LS, alone or in combination with the established V3-glycan antibody PGT121, in chronically simian-human immunodeficiency virus (SHIV)-SF162P3-infected macaques. A single dose of N6-LS suppressed plasma viral loads in 4 out of 5 animals at day 7, while the combination of both antibodies suppressed all animals. The combination of both antibodies had no additive antiviral effect compared to a single dose of PGT121, potentially reflecting the nearly 10-fold-higher potency of PGT121 against this SHIV. Viral rebound occurred in the majority of suppressed animals and was linked to declining plasma bnAb levels over time. In addition to the effect on plasma viremia, bnAb administration resulted in significantly reduced proviral DNA levels in PBMCs after 2 weeks and in lymph nodes after 10 weeks. Autologous neutralizing antibody (nAb) responses and CD8 T-cell responses were not significantly enhanced in the bnAb-treated animals compared to control animals, arguing against their contribution to the viral effects observed. These results confirm the robust antiviral activity of N6-LS , supporting the further clinical development of this antibody. Monocloncal antibodies (MAbs) are being considered for passive immunotherapy of HIV-1 infection. A critical requirement for such strategies is the identification of MAbs that recognize the diversity of variants within circulating but also reservoir viruses, and MAb combinations might be needed to achieve this goal. This study evaluates the novel bnAb N6-LS alone or in combination with the bnAb PGT121, in rhesus macaques that were chronically infected with SHIV. The results demonstrate that N6-LS potently suppressed plasma viral loads in the majority of animals but that the combination with PGT121 was not superior to PGT121 alone in delaying time to viral rebound or reducing peripheral blood mononuclear cell (PBMC) or lymph node proviral DNA levels. The occurrence of viral escape variants in an N6-LS-monotreated animal, however, argues for the need to maximize breadth and antiviral efficacy by combining bnAbs for therapeutic indications.
针对HIV-1的被动免疫疗法很可能需要具有最大广度和效力的广泛中和抗体（bnAbs），以确保治疗效果。最近，新型CD4结合位点抗体N6对大量跨亚型假病毒表现出非凡的中和广度和效力。我们评估了N6-LS单独或与已有的V3-聚糖抗体PGT121联合使用时，在慢性感染猿猴免疫缺陷病毒（SHIV）-SF162P3的猕猴中的抗病毒活性。单剂量的N6-LS在第7天时使5只动物中的4只血浆病毒载量受到抑制，而两种抗体联合使用则抑制了所有动物的病毒载量。与单剂量的PGT121相比，两种抗体联合使用没有额外的抗病毒效果，这可能反映出PGT121对这种SHIV的效力高出近10倍。大多数受到抑制的动物出现了病毒反弹，这与血浆中bnAb水平随时间下降有关。除了对血浆病毒血症的影响外，给予bnAb后2周外周血单核细胞（PBMC）中的前病毒DNA水平以及10周后淋巴结中的前病毒DNA水平均显著降低。与对照动物相比，接受bnAb治疗的动物中自体中和抗体（nAb）反应和CD8 T细胞反应并未显著增强，这表明它们对所观察到的病毒效应没有贡献。这些结果证实了N6-LS强大的抗病毒活性，支持该抗体的进一步临床开发。单克隆抗体（MAbs）正被考虑用于HIV-1感染的被动免疫治疗。此类策略的一个关键要求是鉴定能够识别循环病毒以及潜伏病毒中各种变体的单克隆抗体，可能需要单克隆抗体组合来实现这一目标。本研究评估了新型bnAb N6-LS单独或与bnAb PGT121联合使用，在慢性感染SHIV的恒河猴中的效果。结果表明，N6-LS在大多数动物中有效抑制了血浆病毒载量，但与PGT121联合使用在延迟病毒反弹时间或降低外周血单核细胞（PBMC）或淋巴结前病毒DNA水平方面并不优于单独使用PGT121。然而，在一只接受N6-LS单药治疗的动物中出现了病毒逃逸变体，这表明对于治疗适应症，需要通过联合bnAbs来最大化广度和抗病毒效果。
