A Molecular Mechanism for Probabilistic Bet-hedging and its Role in Viral Latency

Abstract

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. Super-resolution 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.SIGNIFICANCEProbabilistic bet hedging is a generalized diversification strategy to maximize fitness in unpredictable environments, and has been proposed as an evolutionary basis for herpesvirus latency. However, the molecular mechanisms enabling probabilistic bet hedging have remained elusive. Here, we find that the human herpesvirus cytomegalovirus—a major cause of birth defects and transplant failures—utilizes stochastic variability in the abundance of a protein packaged into individual viral particles to enable probabilistic bet hedging between alternate viral states.

Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation

“…These findings collectively, and not surprisingly, indicate that the repression of gene expression for latency is multifactorial and complex. Despite the ability of the pp71 tegument protein to stimulate viral gene expression by antagonizing Daxx, pp71 fails to traffic to the nucleus and degrade Daxx in cells that support latency (Saffert et al, 2010 ), a restriction that is overcome by higher multiplicities of infection or virions with high levels of pp71 (Woodhall et al, 2006 ; Chaturvedi et al, 2020 ).…”

The molecular principles governing HCMV infection outcome

“…4i). Our inability to detect variations that are associated with induction of viral gene expression, likely reflects the relatively homogenous nature of the cells we used and therefore small differences in gene expression are likely masked by other factors, such as the amount of incoming virions which varies between cells 29 , or variability between the content of virions 30 , both which likely play a major role in setting infection outcome.…”

“…This possibly points to the ability to commence substantial viral DNA replication as the genuine step that determines infection outcome. The lack of a clear cellular gene expression signature that is associated with the initial increase in viral gene expression levels, indicates that in this experimental set-up, infection outcome is not dictated by variations in the cellular transcriptome and is likely mostly determined by the amount of infectious virus entering the cell 29 , which will have significant consequences on the initial induction of viral gene transcription or possibly by variability between virion particles 30 .…”

Phenotypic plasticity through disposable genetic adaptation in ciliates

“…Various molecular mechanisms exist to constitutively generate phenotypic heterogeneity for a given genotype, allowing organisms to persist in fluctuating environments [18]. Well-characterized examples of bet-hedging include persisters in bacteria [19], and viral latency [20]. A bet-hedging strategy is not exclusive and heterogeneity can be fine-tuned by phenotypic plasticity, such as in amphicarpic annual seeds [21].…”