The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN’s receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host-cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long-term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.

中文翻译：

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免疫功能低下个体肺部感染期间人类副流感病毒的进化促进病毒持续存在

呼吸道病毒在呼吸道内进行进化的能力提高了在宿主环境或药物治疗的选择压力下进化的可能性。免疫功能低下的宿主中的长期感染是病毒进化和传染性变体发展的潜在驱动因素。我们发现，在免疫功能低下的个体中，慢性人类副流感病毒 3 (HPIV3) 感染的宿主内进化引发了有利于病毒进入和持续存在的突变，这表明类似的过程可能在有包膜的呼吸道病毒中起作用。我们分析了 2 名免疫功能低下个体的纵向 HPIV3 感染，这些感染持续了 278 天和 98 天。HPIV3 附着蛋白血凝素-神经氨酸酶 (HN) 中产生的突变，包括负责激活病毒融合过程的 HN 受体结合位点的第一个体内突变。这种突变的固定与暴露于切割宿主细胞唾液酸部分的药物有关。HN 的纵向适应与促进病毒进入和在细胞中持续存在的特征有关，包括对唾液酸的更高亲和力和更活跃的体外融合活性，但与抗体逃逸无关。因此，长期感染导致突变促进病毒持续存在，这表明以宿主为导向的治疗可能支持病毒的进化，这些病毒改变其生物物理特征以在体内面对这些药物时持续存在。HN 的纵向适应与促进病毒进入和在细胞中持续存在的特征有关，包括对唾液酸的更高亲和力和更活跃的体外融合活性，但与抗体逃逸无关。因此，长期感染导致突变促进病毒持续存在，这表明以宿主为导向的治疗可能支持病毒的进化，这些病毒改变其生物物理特征以在体内面对这些药物时持续存在。HN 的纵向适应与促进病毒进入和在细胞中持续存在的特征有关，包括对唾液酸的更高亲和力和更活跃的体外融合活性，但与抗体逃逸无关。因此，长期感染导致突变促进病毒持续存在，这表明以宿主为导向的治疗可能支持病毒的进化，这些病毒改变其生物物理特征以在体内面对这些药物时持续存在。