Research Article: Lytic Gene Expression Is Frequent in HSV-1 Latent Infection and Correlates with the Engagement of a Cell-Intrinsic Transcriptional Response

Date Published: July 24, 2014

Publisher: Public Library of Science

Author(s): Joel Z. Ma, Tiffany A. Russell, Tim Spelman, Francis R. Carbone, David C. Tscharke, Roger D. Everett.


Herpes simplex viruses (HSV) are significant human pathogens that provide one of the best-described examples of viral latency and reactivation. HSV latency occurs in sensory neurons, being characterized by the absence of virus replication and only fragmentary evidence of protein production. In mouse models, HSV latency is especially stable but the detection of some lytic gene transcription and the ongoing presence of activated immune cells in latent ganglia have been used to suggest that this state is not entirely quiescent. Alternatively, these findings can be interpreted as signs of a low, but constant level of abortive reactivation punctuating otherwise silent latency. Using single cell analysis of transcription in mouse dorsal root ganglia, we reveal that HSV-1 latency is highly dynamic in the majority of neurons. Specifically, transcription from areas of the HSV genome associated with at least one viral lytic gene occurs in nearly two thirds of latently-infected neurons and more than half of these have RNA from more than one lytic gene locus. Further, bioinformatics analyses of host transcription showed that progressive appearance of these lytic transcripts correlated with alterations in expression of cellular genes. These data show for the first time that transcription consistent with lytic gene expression is a frequent event, taking place in the majority of HSV latently-infected neurons. Furthermore, this transcription is of biological significance in that it influences host gene expression. We suggest that the maintenance of HSV latency involves an active host response to frequent viral activity.

Partial Text

Herpes simplex virus (HSV) is a ubiquitous human pathogen that initially replicates in skin and mucosal surfaces prior to establishing an infection in sensory neurons [1]. There, HSV persists life-long with periods of prolonged quiescence punctuated by occasional episodes of reactivation, which may result in recrudescence of disease. As a consequence, HSV has long been viewed as establishing the prototypic latent infection, with minimal antigen expression and little to no active virus production during this phase of infection. While in humans, latency can be short-lived with multiple and frequent bouts of virus reactivation [2], in mice it is especially profound [3], [4], making them the ideal model for detailed examination of this feature. Despite this general stability, one part of the HSV genome has long been known to be active in at least a fraction of neurons, giving rise to the expression of non-coding latency-associated transcripts (LAT) [5], [6]. These transcripts have been postulated to play various roles in latency and this region is also the source of miRNAs that may also modulate infection [7]–[13]. In addition, there is sporadic, but consistent evidence that the transcription of genes normally associated with lytic replication also occurs in sensory ganglia during HSV latency, albeit at far lower levels than LAT [14]–[22]. There are competing explanations for the presence of these lytic transcripts. On the one hand, the lytic products may simply represent sporadic occurrences of complete reactivation, but at frequencies too low to permit ready detection of infectious virus or result in recrudescent disease [23]. An alternative proposal is that lytic transcripts are more widespread, found in a high proportion of infected cells during latency, but they represent abortive reactivation events that fail to progress to productive infection due to additional host control mechanisms [14], [24]. Finally it is possible that these transcripts are simply the result of less than total silencing of the HSV genome, but are of no wider biological consequence.

Long-term HSV infection in mice is generally viewed as a model of profound latency, with few, if any, of the spontaneous reactivation episodes seen in other species and virtually no active production of virus once the lytic phase of infection is extinguished. In the context of this model of stable latency, the frequency with which transcripts consistent with lytic gene expression were found here is striking. Whilst our data does not break ground in terms of the detection of viral transcripts from outside the LAT region during latency, that this might happen so often has previously been only a matter of conjecture [14]. Perhaps more importantly, we also show that the host is equally active in responding to this viral activity, demonstrating that the viral transcription has biological consequences.




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