Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases ≫ (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France.
Viral Evolution and Transmission Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
EBioMedicine. 2020 Jul;57:102842. doi: 10.1016/j.ebiom.2020.102842. Epub 2020 Jun 30.
HIV-1 sexual transmission occurs mostly through infected semen, which contains both free virions and infected leukocytes. Transmission initiated by infected cells has been shown by several in vitro and in vivo studies and a reduced capacity of broadly neutralizing antibodies (bNAbs) to inhibit cell-to-cell transmission has also been reported. However, due to limitations of available experimental models, there is yet no clarity to which extend bNAbs can prevent transmission mediated by semen leukocytes.
We developed a novel in vitro assay to measure cell-cell transmission that makes use of splenocytes or CD45 semen leukocytes collected from acutely SHIV-infected cynomolgus macaques. A panel of 11 bNAbs was used either alone or in combination to assess their inhibitory potential against both cell-free and cell-cell infection.
Splenocytes and semen leucocytes displayed a similar proportion of CD4T-cell subsets. Either cell type transferred infection in vitro to target TZM-bl cells and PBMCs. Moreover, infection of macaques was achieved following intravaginal challenge with splenocytes. The anti-N-glycans/V3 loop bNAb 10-1074 was highly efficient against cell-associated transmission mediated by infected spleen cells and its potency was maintained when transmission was mediated by CD45 semen leukocytes.
These results support the use of bNAbs in preventative or therapeutic studies aiming to block transmission events mediated not only by free viral particles but also by infected cells. Our experimental system could be used to predict in vivo efficacy of bNAbs.
This work was funded by the ANRS and the European Commission.
HIV-1 的性传播主要通过含有游离病毒粒子和感染白细胞的感染精液发生。几项体外和体内研究表明，受感染细胞引发的传播已经被证实，而广泛中和抗体（bNAbs）抑制细胞间传播的能力也有所下降。然而，由于现有实验模型的限制，尚不清楚 bNAbs 在多大程度上可以防止精液白细胞介导的传播。
我们开发了一种新的体外测定方法来测量细胞间传播，该方法利用急性 SHIV 感染的食蟹猴的脾细胞或 CD45 精液白细胞。使用了一组 11 种 bNAbs 单独或组合使用，以评估它们对游离和细胞间感染的抑制潜力。
脾细胞和精液白细胞显示出相似比例的 CD4T 细胞亚群。这两种细胞类型都能在体外将感染传递给靶 TZM-bl 细胞和 PBMC。此外，用脾细胞进行阴道内挑战后，感染了猕猴。抗 N-聚糖/V3 环 bNAb 10-1074 对感染的脾细胞介导的细胞相关传播非常有效，当传播由 CD45 精液白细胞介导时，其效力得以维持。
这些结果支持在预防或治疗性研究中使用 bNAbs，以阻止不仅由游离病毒粒子，而且由感染细胞介导的传播事件。我们的实验系统可用于预测 bNAbs 的体内疗效。
这项工作得到了法国国家艾滋病研究署和欧盟委员会的资助。
