Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States of America.
PLoS Comput Biol. 2011 Mar;7(3):e1002015. doi: 10.1371/journal.pcbi.1002015. Epub 2011 Mar 17.
Infectious disease treatments, both pharmaceutical and vaccine, face three universal challenges: the difficulty of targeting treatments to high-risk 'superspreader' populations who drive the great majority of disease spread, behavioral barriers in the host population (such as poor compliance and risk disinhibition), and the evolution of pathogen resistance. Here, we describe a proposed intervention that would overcome these challenges by capitalizing upon Therapeutic Interfering Particles (TIPs) that are engineered to replicate conditionally in the presence of the pathogen and spread between individuals--analogous to 'transmissible immunization' that occurs with live-attenuated vaccines (but without the potential for reversion to virulence). Building on analyses of HIV field data from sub-Saharan Africa, we construct a multi-scale model, beginning at the single-cell level, to predict the effect of TIPs on individual patient viral loads and ultimately population-level disease prevalence. Our results show that a TIP, engineered with properties based on a recent HIV gene-therapy trial, could stably lower HIV/AIDS prevalence by ∼30-fold within 50 years and could complement current therapies. In contrast, optimistic antiretroviral therapy or vaccination campaigns alone could only lower HIV/AIDS prevalence by <2-fold over 50 years. The TIP's efficacy arises from its exploitation of the same risk factors as the pathogen, allowing it to autonomously penetrate superspreader populations, maintain efficacy despite behavioral disinhibition, and limit viral resistance. While demonstrated here for HIV, the TIP concept could apply broadly to many viral infectious diseases and would represent a new paradigm for disease control, away from pathogen eradication but toward robust disease suppression.
传染病的治疗方法（包括药物和疫苗）都面临着三个普遍的挑战：难以针对高风险的“超级传播者”人群进行治疗，这些人是导致绝大多数疾病传播的主要因素；宿主人群中存在行为障碍（例如依从性差和风险抑制减弱）；病原体耐药性的进化。在这里，我们描述了一种建议的干预措施，该措施利用了在病原体存在的情况下能够有条件复制并在个体之间传播的治疗性干扰颗粒（TIPs），类似于具有活减毒疫苗的“可传播免疫”（但没有恢复毒力的潜力）。我们基于撒哈拉以南非洲地区的 HIV 实地数据进行分析，构建了一个多尺度模型，从单细胞水平开始，预测 TIPs 对个体患者病毒载量的影响，并最终预测对人群水平疾病流行率的影响。我们的研究结果表明，一种基于最近的 HIV 基因治疗试验的 TIP，在 50 年内可将 HIV/AIDS 的流行率稳定降低约 30 倍，并可与当前的治疗方法互补。相比之下，乐观的抗逆转录病毒治疗或疫苗接种运动仅能在 50 年内将 HIV/AIDS 的流行率降低不到 2 倍。TIP 的功效源于其对病原体相同的风险因素的利用，这使其能够自主渗透超级传播者人群，在行为抑制的情况下保持疗效，并限制病毒耐药性的产生。虽然这里是针对 HIV 进行了演示，但 TIP 的概念可以广泛应用于许多病毒性传染病，并且代表了一种新的疾病控制模式，远离病原体根除，而是转向稳健的疾病抑制。
