Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals

The rapid evolution of RNA-encoded viruses such as HIV presents a major barrier to infectious disease control using conventional pharmaceuticals and vaccines. Previously, it was proposed that defective interfering particles could be developed to indefinitely control the HIV/AIDS pandemic; in individual patients, these engineered molecular parasites were further predicted to be refractory to HIV’s mutational escape (i.e., be ‘resistance-proof’). However, an outstanding question has been whether these engineered interfering particles—termed Therapeutic Interfering Particles (TIPs)—would remain resistance-proof at the population-scale, where TIP-resistant HIV mutants may transmit more efficiently by reaching higher viral loads in the TIP-treated subpopulation. Here, we develop a multi-scale model to test whether TIPs will maintain indefinite control of HIV at the population-scale, as HIV (‘unilaterally’) evolves toward TIP resistance by limiting the production of viral proteins available for TIPs to parasitize. Model results capture the existence of two intrinsic evolutionary tradeoffs that collectively prevent the spread of TIP-resistant HIV mutants in a population. First, despite their increased transmission rates in TIP-treated sub-populations, unilateral TIP-resistant mutants are shown to have reduced transmission rates in TIP-untreated sub-populations. Second, these TIP-resistant mutants are shown to have reduced growth rates (i.e., replicative fitness) in both TIP-treated and TIP-untreated individuals. As a result of these tradeoffs, the model finds that TIP-susceptible HIV strains continually outcompete TIP-resistant HIV mutants at both patient and population scales when TIPs are engineered to express >3-fold more genomic RNA than HIV expresses. Thus, the results provide design constraints for engineering population-scale therapies that may be refractory to the acquisition of antiviral resistance.

以人类免疫缺陷病毒（HIV）为代表的RNA编码病毒的快速演化，给运用传统药物与疫苗开展传染病防控工作带来了重大障碍。此前已有研究提出，可开发缺陷干扰颗粒以长期防控艾滋病（HIV/AIDS）大流行；在个体患者体内，这类工程化分子寄生虫被进一步预测可抵御HIV的突变逃逸，即具备"抗药性"。然而，一个悬而未决的核心问题是，这类被命名为治疗性干扰颗粒（Therapeutic Interfering Particles, TIPs）的工程化干扰颗粒，在群体尺度下是否仍能保持抗药性——在接受TIP治疗的亚群中，对TIP具有抗性的HIV突变株可通过达到更高病毒载量，实现更高效的传播。本研究构建了多尺度模型，用于检验当HIV通过限制可供TIP寄生的病毒蛋白产量，以"单向"路径演化出对TIP的抗性时，TIP能否在群体尺度下长期维持对HIV的防控效果。模型结果揭示了两类内在的演化权衡，二者共同阻止了对TIP具有抗性的HIV突变株在群体中的扩散：其一，尽管在接受TIP治疗的亚群中，这类单向抗性突变株的传播速率有所提升，但在未接受TIP治疗的亚群中，其传播速率反而出现下降；其二，这类抗性突变株在接受TIP治疗与未接受治疗的个体中，其生长速率（即复制适合度）均有所降低。基于这两类演化权衡，模型发现当TIP被工程化设计为表达的基因组RNA量超过HIV的3倍以上时，无论是在个体患者尺度还是群体尺度下，对TIP敏感的HIV毒株始终能够竞争性排除抗性突变株。因此，本研究结果为开发可抵御抗病毒抗性获得的群体尺度治疗方案提供了设计约束条件。