Faculty of Computational Mathematics and Cybernetics, Lomonosov Moscow State University, Moscow, Russia.
Marchuk Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia.
PLoS Comput Biol. 2019 Nov 6;15(11):e1007401. doi: 10.1371/journal.pcbi.1007401. eCollection 2019 Nov.
The novel therapies with immune checkpoint inhibitors hold great promises for patients with chronic virus infections and cancers. This is based mainly on the partial reversal of the exhausted phenotype of antigen-specific cytotoxic CD8 T cells (CTL). Recently, we have shown that the restoration of HIV-specific T cell function depends on the HIV infection stage of an infected individual. Here we aimed to answer two fundamental questions: (i) Can one estimate growth parameters for the HIV-specific proliferative responsiveness upon PD-L1 blockade ex vivo? (ii) Can one use these parameter estimates to predict clinical benefit for HIV-infected individuals displaying diverse infection phenotypes? To answer these questions, we first analyzed HIV-1 Gag-specific CD8 T cell proliferation by time-resolved CFSE assays and estimated the effect of PD-L1 blockade on division and death rates, and specific precursor frequencies. These values were then incorporated into a model for CTL-mediated HIV control and the effects on CTL frequencies, viral loads and CD4 T cell counts were predicted for different infection phenotypes. The biggest absolute increase in CD4 T cell counts was in the group of slow progressors while the strongest reduction in virus loads was observed in progressor patients. These results suggest a significant clinical benefit only for a subgroup of HIV-infected individuals. However, as PD1 is a marker of lymphocyte activation and expressed on several lymphocyte subsets including also CD4 T cells and B cells, we subsequently examined the multiple effects of anti-PD-L1 blockade beyond those on CD8 T cells. This extended model then predicts that the net effect on HIV load and CD4 T cell number depends on the interplay between positive and negative effects of lymphocyte subset activation. For a physiologically relevant range of affected model parameters, PD-L1 blockade is likely to be overall beneficial for HIV-infected individuals.
新型免疫检查点抑制剂疗法为慢性病毒感染和癌症患者带来了新的希望。这主要基于抗原特异性细胞毒性 CD8 T 细胞（CTL）耗竭表型的部分逆转。最近，我们已经表明，HIV 特异性 T 细胞功能的恢复取决于感染个体的 HIV 感染阶段。在这里，我们旨在回答两个基本问题：（i）能否在体外通过 PD-L1 阻断估计 HIV 特异性增殖反应的生长参数？（ii）能否使用这些参数估计来预测具有不同感染表型的 HIV 感染个体的临床获益？为了回答这些问题，我们首先通过时间分辨 CFSE 测定分析了 HIV-1 Gag 特异性 CD8 T 细胞的增殖，并估计了 PD-L1 阻断对分裂和死亡率以及特定前体频率的影响。然后，这些值被纳入 CTL 介导的 HIV 控制模型中，并预测了不同感染表型对 CTL 频率、病毒载量和 CD4 T 细胞计数的影响。CD4 T 细胞计数的绝对值增加最大的是缓慢进展者，而病毒载量的下降最强的是进展者患者。这些结果表明，只有一小部分 HIV 感染个体具有显著的临床获益。然而，由于 PD1 是淋巴细胞激活的标志物，并且在包括 CD4 T 细胞和 B 细胞在内的几个淋巴细胞亚群上表达，因此我们随后检查了抗 PD-L1 阻断对除 CD8 T 细胞以外的多个淋巴细胞亚群的影响。这个扩展模型预测，HIV 载量和 CD4 T 细胞数量的净效应取决于淋巴细胞亚群激活的正负效应之间的相互作用。对于生理相关的模型参数范围，PD-L1 阻断很可能对 HIV 感染个体总体有益。
