Project Summary
New experimental models are needed to develop treatments for varicella zoster virus (VZV), a
DNA virus that has infected over 90% of individuals worldwide. Primary infection causes chickenpox,
while reactivation of the virus within the nervous system can have dire consequences. Encephalitis is
the most fearsome complication, and VZV represents one of the most common infectious causes of
encephalitis worldwide. Shingles (herpes zoster) is the most common manifestation of viral
reactivation, affecting one out of every three people in the U.S. and causing post-herpetic neuralgia
(PHN), a severe, often chronic, pain syndrome with annual U.S. costs of over $1 billion. Importantly,
VZV continues to exact a marked toll despite the advent and widespread use of antiviral agents
(acyclovir) and vaccination, which only afford partial protection and do not specifically address PHN.
Thus, new therapies are needed to limit the morbidity and mortality associated with neuronal infection
and reactivation.
The major limitation in the study of VZV infection is the strict species-specificity of the virus, as
it essentially exclusively infects human cells. As a result, there are no robust animal models that
recapitulate essential features of human disease. Moreover, the virus appears to utilize distinct
cellular and molecular pathways in different cell types. Thus, studies of viral infection in human
fibroblasts or other skin cells may not directly bear on pathogenesis within human neurons. Recently,
VZV has been shown to infect neurons derived from human neural stem cells and human pluripotent
stem cells, suggesting that stem-cell based approaches for the study of VZV pathogenesis are likely
to hold great promise for the development of new treatments. However, most human neuronal
cultures systems derived from stem cells are typically comprised of few, if any, sensory neurons.
This is a great limitation since sensory neurons are the main cell type in which the virus establishes
latency and later re-emerges during reactivation.
Recently, we have developed a human pluripotent stem cell based model of sensory neuron
infection by VZV, in which the neurons are capable of harboring VZV in a latent state. We anticipate
that this model will allow characterization of cellular and molecular mechanisms of latency and will
serve as the basis to develop new treatments for VZV reactivation.