Robertson Alexander J, Kerr Benjamin, Feder Alison F
Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98103.
Department of Biology, University of Washington, Seattle, WA 98103.
bioRxiv. 2025 May 26:2025.05.20.655113. doi: 10.1101/2025.05.20.655113.
Antiviral resistance evolution poses a major obstacle for controlling viral infections. A promising strategy is to target shared viral proteins that allow drug susceptible viruses to sensitize resistant ones during cellular coinfection, muting selection for resistance. Pocapavir, a poliovirus capsid inhibitor, employs this sociovirological strategy. While susceptible viruses significantly suppressed resistance in the presence of pocapavir in cell culture, a pocapavir clinical trial observed widespread resistance evolution and limited improvements to clearance times. To reconcile these findings, we present an intra-host eco-evolutionary model of poliovirus in the presence of pocapavir, which reproduces both the potent interference observed and the resistance emergence seen in patients. In the short term, our model predicts that a high density of susceptible viruses sensitizes resistant ones to pocapavir, mirroring cell culture results. However, over multiple replication cycles, pocapavir's high potency collapses viral density, which reduces coinfection and allows resistance to evolve as observed in the clinical trial. Since coinfection is essential to suppress resistance, enabling greater survival of susceptible viruses could offer therapeutic advantages. Counterintuitively, we demonstrate that this can be achieved by antiviral potency, which can limit resistance evolution while also maintaining a low viral load. These findings suggest that antivirals that rely on viral social interaction must balance immediate neutralization with the preservation of future coinfection, yielding more sustained inhibition. Explicitly considering the eco-evolutionary feedback encompassing viral density, social phenotypes and absolute fitness not only provides new insights into designing effective therapies but also illuminates viral evolutionary dynamics more broadly.
抗病毒耐药性的演变是控制病毒感染的一个主要障碍。一种有前景的策略是靶向共享的病毒蛋白，使药物敏感病毒在细胞共感染期间使耐药病毒敏感化，从而抑制耐药性的选择。波卡帕韦是一种脊髓灰质炎病毒衣壳抑制剂，采用了这种社会病毒学策略。虽然在细胞培养中，敏感病毒在波卡帕韦存在的情况下显著抑制了耐药性，但一项波卡帕韦临床试验观察到广泛的耐药性演变以及清除时间的有限改善。为了调和这些发现，我们提出了一个在波卡帕韦存在情况下脊髓灰质炎病毒的宿主内生态进化模型，该模型再现了所观察到的强效干扰以及患者中出现的耐药性。在短期内，我们的模型预测高浓度的敏感病毒会使耐药病毒对波卡帕韦敏感，这与细胞培养结果一致。然而，在多个复制周期中，波卡帕韦的高效力使病毒密度下降，这减少了共感染，并使耐药性如临床试验中所观察到的那样进化。由于共感染对于抑制耐药性至关重要，使敏感病毒有更大的存活率可能具有治疗优势。与直觉相反的是，我们证明这可以通过抗病毒效力来实现，抗病毒效力可以限制耐药性的进化，同时也能维持低病毒载量。这些发现表明，依赖病毒社会相互作用的抗病毒药物必须在即时中和与保留未来共感染之间取得平衡，从而产生更持久的抑制作用。明确考虑包括病毒密度、社会表型和绝对适合度在内的生态进化反馈，不仅为设计有效疗法提供了新的见解，而且更广泛地阐明了病毒进化动力学。
