Chaturvedi Sonali, Klein Jonathan, Vardi Noam, Bolovan-Fritts Cynthia, Wolf Marie, Du Kelvin, Mlera Luwanika, Calvert Meredith, Moorman Nathaniel J, Goodrum Felicia, Huang Bo, Weinberger Leor S
Gladstone Institute for Virology and Immunology, Gladstone|University of California, San Francisco Center for Cell Circuitry, San Francisco, CA 94158.
Department of Cell & Molecular Medicine, University of Arizona, Tucson, AZ 85721.
Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17240-17248. doi: 10.1073/pnas.1914430117. Epub 2020 Jul 6.
Probabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Superresolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein-the major viral transactivator protein-exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.
概率性风险对冲是一种通过使表型变异性与环境变异性相匹配，从而在不可预测的环境中最大化适应性的策略，理论上它可以解释包括病毒潜伏在内的各种命运决定的进化。然而，风险对冲背后的分子机制仍不清楚。在这里，我们报告称，单个疱疹病毒病毒粒子内蛋白质丰度的巨大变异性使得病毒复制和潜伏之间能够进行概率性风险对冲。对人类疱疹病毒巨细胞病毒（CMV）单个病毒粒子的超分辨率成像显示，主要病毒反式激活蛋白pp71被膜蛋白在病毒粒子之间的水平表现出极大的变异性。这种超泊松分布的被膜变异性促进了交替的复制策略：病毒粒子中高pp71水平增强了病毒的复制适应性，但令人惊讶的是，阻碍了沉默，而低病毒粒子pp71水平降低了适应性，但促进了沉默。总体而言，结果表明随机的被膜包装提供了一种机制，可以在病毒复制和潜伏之间进行概率性风险对冲。
