Mittal Soumya, Garg Amar K, Desikan Rajat, Dixit Narendra M
Department of Chemical Engineering, Indian Institute of Science, Bangalore 560012, India.
Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India.
J R Soc Interface. 2024 Dec;21(221):20240535. doi: 10.1098/rsif.2024.0535. Epub 2024 Dec 4.
Antibody therapy for HIV-1 infection exerts two broad effects: a drug-like, antiviral effect, which rapidly lowers the viral load, and a vaccinal effect, which may control the viral load long-term by improving the immune response. Here, we elucidate a trade-off between these two effects as they pertain to the humoral response, which may compromise antibody therapy aimed at eliciting long-term HIV-1 remission. We developed a multi-scale computational model that combined within-host viral dynamics and stochastic simulations of the germinal centre (GC) reaction, enabling simultaneous quantification of the antiviral and vaccinal effects of antibody therapy. The model predicted that increasing antibody dosage or antibody-antigen affinity increased immune complex formation and enhanced GC output. Beyond a point, however, a strong antiviral effect reduced antigen levels substantially, extinguishing GCs and limiting the humoral response. We found signatures of this trade-off in clinical studies. Accounting for the trade-off could be important in optimizing antibody therapy for HIV-1 remission.
针对HIV-1感染的抗体疗法具有两种广泛的作用：一种类似药物的抗病毒作用，可迅速降低病毒载量；另一种是疫苗样作用，可通过改善免疫反应长期控制病毒载量。在此，我们阐明了这两种作用在体液反应方面的权衡，这可能会损害旨在实现HIV-1长期缓解的抗体疗法。我们开发了一种多尺度计算模型，该模型结合了宿主内病毒动力学和生发中心（GC）反应的随机模拟，能够同时量化抗体疗法的抗病毒和疫苗样作用。该模型预测，增加抗体剂量或抗体-抗原亲和力会增加免疫复合物的形成并增强GC输出。然而，超过某一点后，强大的抗病毒作用会大幅降低抗原水平，使GC消失并限制体液反应。我们在临床研究中发现了这种权衡的迹象。在优化针对HIV-1缓解的抗体疗法时，考虑这种权衡可能很重要。
