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，Human Immunodeficiency Virus）为代表的RNA编码病毒的快速演化，给使用传统药物与疫苗防控传染病带来了重大阻碍。此前已有研究提出，可开发缺陷干扰颗粒（defective interfering particles，DIP）以长期防控HIV/AIDS（艾滋病，Acquired Immunodeficiency Syndrome）大流行；在个体患者体内，这类经工程改造的分子寄生虫还被预测可抵御HIV的突变逃逸，即具备“抗耐药性”。然而，一个悬而未决的核心问题是：这类经工程改造的干扰颗粒——即治疗性干扰颗粒（Therapeutic Interfering Particles，TIPs）——在群体层面是否仍能保持抗耐药性？在接受TIPs治疗的亚人群中，携带TIPs耐药突变的HIV毒株可通过提升病毒载量实现更高效的传播。本研究构建了多尺度模型，以验证当HIV通过限制可被TIPs寄生的病毒蛋白合成，“单向”演化出对TIPs的耐药性时，TIPs能否在群体层面长期防控HIV。模型结果揭示了两类内在的演化权衡机制，二者共同阻碍了TIPs耐药HIV毒株在群体中的传播。其一，尽管这类单向演化的TIPs耐药毒株在接受TIPs治疗的亚人群中传播效率更高，但在未接受TIPs治疗的亚人群中，其传播速率反而有所降低。其二，这类TIPs耐药毒株在接受与未接受TIPs治疗的个体体内，其生长速率（即复制适合度）均出现下降。基于上述权衡机制，模型结果显示：当TIPs经工程改造后表达的基因组RNA量是HIV的3倍以上时，对TIPs敏感的HIV毒株在个体与群体层面均能持续胜过TIPs耐药毒株。综上，本研究结果为开发可抵御抗病毒耐药性产生的群体层面治疗方案提供了设计约束条件。