Research ArticleHerpes Simplex Virus

Frequent Release of Low Amounts of Herpes Simplex Virus from Neurons: Results of a Mathematical Model

Science Translational Medicine  18 Nov 2009:
Vol. 1, Issue 7, pp. 7ra16
DOI: 10.1126/scitranslmed.3000193

You are currently viewing the editor's summary.

View Full Text

Log in


Insights from Modeling Herpes Virus Behavior

One variety of the herpes simplex virus (HSV-2) infects 45 million people worldwide, often causing ulcers in the genital region, and increases the acquisition and transmission of HIV. Herpes is passed from person to person through sexual contact. After the initial infection, the herpes virus resides in the cell bodies of neurons that innervate the genital tract, sometimes causing recurrences of the painful genital blisters. With newer, highly sensitive methods of detecting the virus by the polymerase chain reaction, the pattern of HSV-2 shedding in the genital tract was unexpectedly revealed to include frequent, intermittent episodes of variable amounts of virus, not just the periodic larger episodes that had been assumed to cause the sporadic recurrence of genital ulcers. This finding has been of concern for several reasons: The likelihood of transmitting the virus to a sexual partner is higher if herpes virus is often present in the genital tract of infected people. And worse, most episodes of release of the small amounts of virus are not accompanied by any symptoms, so infected individuals are often unaware of their own infectious state.

A clearer understanding of how virus release into the genital tract is controlled and when it causes an active ulcer is needed to develop better ways to combat this common infection. Available treatments, mainly antiviral agents, can only limit spread and accelerate healing but do not completely eliminate asymptomatic shedding or transmission. Because informative experiments are difficult to do in humans, Schiffer et al. developed a mathematical model of HSV-2 infection of mucosal tissue. Their model—which incorporated virus release to the genital mucosal tissue, infection of epithelial cells, replication of virus within epithelial cells, and an immune response—faithfully replicated shedding episode data from anogenital swabs from 89 patients and from lesions of 15 more patients. It predicted that infected epithelial cells can generate hundreds of times more virus than the infected neurons, accounting for detectable shedding episodes. A stochastic version of the model predicted variability in the patterns of herpes infection seen in patients with respect to the percentage of time spent shedding and the lesion diameter. The model also suggested that there are many clinical episodes of viral shedding that cannot be detected by current methods. Most important, the analysis led the authors to conclude that neurons releasing only a few copies of herpes virus each day can cause the characteristic periodic outbreaks of painful ulcers and that it is the amount of virus released per unit time, not the frequency of release, that controls how often detectable virus appears in the genital tract. The authors used both patient data and the cellular biology of herpes infection to build an informative model that has revealed a control point for a key determinant of viral infectivity, suggesting a vulnerable target for therapeutic intervention.

Footnotes