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Pathogens 2017, 6(2), 24; doi:10.3390/pathogens6020024

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

1
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
2
Department of Neurosurgery, New York University School of Medicine, New York, NY 10016, USA
3
Kimmel Center for Stem Cell Biology, New York University School of Medicine, New York, NY 10016, USA
4
Brain Tumor Center, New York University School of Medicine, New York, NY 10016, USA
5
Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA
6
Neuroscience Institute, New York University School of Medicine, New York, NY 10016, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Christopher C. Broder
Received: 12 May 2017 / Revised: 2 June 2017 / Accepted: 6 June 2017 / Published: 8 June 2017
(This article belongs to the Special Issue Herpesviruses)
View Full-Text   |   Download PDF [1933 KB, uploaded 8 June 2017]   |  

Abstract

Herpes simplex virus 1 (HSV-1) uses latency in peripheral ganglia to persist in its human host, however, recurrent reactivation from this reservoir can cause debilitating and potentially life-threatening disease. Most studies of latency use live-animal infection models, but these are complex, multilayered systems and can be difficult to manipulate. Infection of cultured primary neurons provides a powerful alternative, yielding important insights into host signaling pathways controlling latency. However, small animal models do not recapitulate all aspects of HSV-1 infection in humans and are limited in terms of the available molecular tools. To address this, we have developed a latency model based on human neurons differentiated in culture from an NIH-approved embryonic stem cell line. The resulting neurons are highly permissive for replication of wild-type HSV-1, but establish a non-productive infection state resembling latency when infected at low viral doses in the presence of the antivirals acyclovir and interferon-α. In this state, viral replication and expression of a late viral gene marker are not detected but there is an accumulation of the viral latency-associated transcript (LAT) RNA. After a six-day establishment period, antivirals can be removed and the infected cultures maintained for several weeks. Subsequent treatment with sodium butyrate induces reactivation and production of new infectious virus. Human neurons derived from stem cells provide the appropriate species context to study this exclusively human virus with the potential for more extensive manipulation of the progenitors and access to a wide range of preexisting molecular tools. View Full-Text
Keywords: herpes simplex virus; HSV-1; alphaherpesvirus; human; primary neurons; latency; reactivation; embryonic stem cells herpes simplex virus; HSV-1; alphaherpesvirus; human; primary neurons; latency; reactivation; embryonic stem cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Pourchet, A.; Modrek, A.S.; Placantonakis, D.G.; Mohr, I.; Wilson, A.C. Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons. Pathogens 2017, 6, 24.

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