Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys
Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys
复制标题
DOI：
10.1128/jvi.00498-17
复制
发表时间：
2017-08-01
影响因子：
5.4
通讯作者：
Barouch, Dan H.
中科院分区：
文献类型：
--
作者：
Julg, Boris;Pegu, Amarendra;Barouch, Dan H.
针对HIV-1的被动免疫疗法很可能需要具有最大宽度和效力的广泛中和抗体（bnAb），以确保治疗效果。最近，新的CD 4结合位点抗体N6显示出针对大组交叉进化枝假病毒的非凡中和宽度和效力。我们在慢性猴-人免疫缺陷病毒（SHIV）-SF 162 P3感染的猕猴中评价了N6-LS单独或与已建立的V3-聚糖抗体PGT 121联合的体内抗病毒活性。在第7天，N6-LS单次给药抑制了5只动物中的4只的血浆病毒载量，而两种抗体的组合抑制了所有动物。与单剂量的PGT 121相比，两种抗体的组合没有相加的抗病毒作用，这可能反映了PGT 121针对该SHIV的效力高出近10倍。病毒反弹发生在大多数抑制动物中，并与血浆bnAb水平随时间下降有关。除了对血浆病毒血症的影响外，bnAb给药还导致2周后PBMC和10周后淋巴结中的前病毒DNA水平显著降低。与对照动物相比，bnAb治疗动物的自体中和抗体（nAb）反应和CD 8（+）T细胞反应并未显着增强，这与它们对观察到的病毒效应的贡献相反。这些结果证实了N6-LS在体内的强大抗病毒活性，支持该抗体的进一步临床开发。重要性单克隆抗体（MAb）正在考虑用于HIV-1感染的被动免疫治疗。这种策略的关键要求是鉴定识别循环病毒和储库病毒内变异多样性的单克隆抗体，并且可能需要单克隆抗体组合来实现这一目标。本研究在慢性感染SHIV的恒河猴中评价了单独的新型bnAb N6-LS或与bnAb PGT 121的组合。结果表明，在大多数动物中，N6-LS有效抑制血浆病毒载量，但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，与PGT 121联合用药并不上级单独使用PGT 121。然而，在N6-LS单药治疗的动物中病毒逃逸变体的发生证明需要通过组合bnAb用于治疗适应症来最大化广度和抗病毒功效。
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 in vivo 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 in vivo, supporting the further clinical development of this antibody.IMPORTANCE 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.