Phylodynamic analysis of the emergence and epidemiological impact of transmissible defective dengue viruses.
Phylodynamic analysis of the emergence and epidemiological impact of transmissible defective dengue viruses.
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DOI：
10.1371/journal.ppat.1003193
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Lloyd-Smith JO
中科院分区：
文献类型：
--
作者：
Ke R;Aaskov J;Holmes EC;Lloyd-Smith JO
来自RNA病毒的宿主内序列数据揭示了缺陷病毒在天然病毒群体中的普遍存在，有时频率高得令人惊讶。尽管实验室病毒学家早就知道有缺陷的病毒，但它们在临床和流行病学环境中的相关性尚未确定。2001年首次在缅甸发现1型登革病毒（DENV-1）缺陷谱系的长期传播，提出了关于可传播缺陷病毒的出现及其在病毒流行病学中的作用的重要问题。通过结合系统发育分析和动力学建模，我们研究了宿主内和宿主间尺度上的进化和生态过程如何塑造了有缺陷的DENV-1谱系的出现和传播。我们发现，这个谱系的缺陷病毒出现在1998年6月和2001年2月之间，并且缺陷病毒主要是通过与功能性病毒共同传播到未感染个体。我们提供的证据表明，令人惊讶的是，这种共同传播途径比单独传播功能性登革热病毒具有更高的传播潜力。因此，我们预测，有缺陷的谱系应增加登革热感染的总体发病率，这可能是2001-2002年缅甸登革热发病率历史性高的原因。我们的研究结果表明，缺陷病毒可能通过改变毒力-传播性权衡来影响人类病原体的流行病学，或者以自身的方式作为循环感染出现。他们还证明了病毒变体之间的相互作用，如互补作用，可以为病毒的出现开辟新的途径。缺陷病毒是具有基因突变或缺失的病毒颗粒，这些基因突变或缺失消除了基本功能，因此它们不能独立完成其生命周期。它们只能通过用功能性病毒共同感染宿主细胞并“借用”它们的功能元件来繁殖。已观察到许多人类病原体的缺陷病毒，但认为它们不会影响流行病学结果。最近有报告说，2001-2002年，一种缺陷型登革热病毒在缅甸通过人类和蚊子传播了至少18个月。在这项研究中，我们调查的出现和流行病学的影响，这种有缺陷的血统相结合的遗传序列分析与数学模型。我们发现，缺陷谱系出现于1998年6月至2001年2月之间的登革热病毒循环，它的传播，因为令人惊讶的是，它的存在导致功能性登革热病毒更有效地传播。我们的模型表明，这将导致登革热感染总数大幅上升，与2001年和2002年缅甸报告的登革热病例的历史高水平一致。我们的研究对登革热病毒的生物学产生了新的见解，并证明了缺陷病毒影响传染病流行病学的潜力。
Intra-host sequence data from RNA viruses have revealed the ubiquity of defective viruses in natural viral populations, sometimes at surprisingly high frequency. Although defective viruses have long been known to laboratory virologists, their relevance in clinical and epidemiological settings has not been established. The discovery of long-term transmission of a defective lineage of dengue virus type 1 (DENV-1) in Myanmar, first seen in 2001, raised important questions about the emergence of transmissible defective viruses and their role in viral epidemiology. By combining phylogenetic analyses and dynamical modeling, we investigate how evolutionary and ecological processes at the intra-host and inter-host scales shaped the emergence and spread of the defective DENV-1 lineage. We show that this lineage of defective viruses emerged between June 1998 and February 2001, and that the defective virus was transmitted primarily through co-transmission with the functional virus to uninfected individuals. We provide evidence that, surprisingly, this co-transmission route has a higher transmission potential than transmission of functional dengue viruses alone. Consequently, we predict that the defective lineage should increase overall incidence of dengue infection, which could account for the historically high dengue incidence reported in Myanmar in 2001–2002. Our results show the unappreciated potential for defective viruses to impact the epidemiology of human pathogens, possibly by modifying the virulence-transmissibility trade-off, or to emerge as circulating infections in their own right. They also demonstrate that interactions between viral variants, such as complementation, can open new pathways to viral emergence. Defective viruses are viral particles with genetic mutations or deletions that eliminate essential functions, so that they cannot complete their life cycles independently. They can reproduce only by co-infecting host cells with functional viruses and ‘borrowing’ their functional elements. Defective viruses have been observed for many human pathogens, but they have not been thought to impact epidemiological outcomes. Recently it was reported that a lineage of defective dengue virus spread through humans and mosquitoes in Myanmar for at least 18 months in 2001–2002. In this study, we investigate the emergence and epidemiological impact of this defective lineage by combining genetic sequence analyses with mathematical models. We show that the defective lineage emerged from circulating dengue viruses between June 1998 and February 2001, and that it spreads because—surprisingly—its presence causes functional dengue viruses to transmit more efficiently. Our model shows that this would cause a substantial rise in total dengue infections, consistent with historically high levels of dengue cases reported in Myanmar during 2001 and 2002. Our study yields new insights into the biology of dengue virus, and demonstrates a previously unappreciated potential for defective viruses to impact the epidemiology of infectious diseases.
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