Gene editing and elimination of latent herpes simplex virus in vivo

Martine Aubert, Daniel E. Strongin, Pavitra Roychoudhury, Michelle A. Loprieno, Anoria K. Haick, Lindsay M. Klouser, Laurence Stensland, Meei-Li Huang, Negar Makhsous, Alexander Tait, Harshana S. Silva Feelixge, Roman Galetto, Philippe Duchateau, Alexander L. Greninger, Daniel Stone and Keith R. Jerome ()
Additional contact information
Martine Aubert: Fred Hutchinson Cancer Research Center
Daniel E. Strongin: University of Washington
Pavitra Roychoudhury: University of Washington
Michelle A. Loprieno: Fred Hutchinson Cancer Research Center
Anoria K. Haick: Fred Hutchinson Cancer Research Center
Lindsay M. Klouser: Fred Hutchinson Cancer Research Center
Laurence Stensland: University of Washington
Meei-Li Huang: University of Washington
Negar Makhsous: University of Washington
Alexander Tait: University of Washington
Harshana S. Silva Feelixge: Fred Hutchinson Cancer Research Center
Roman Galetto: Cellectis SA
Philippe Duchateau: Cellectis SA
Alexander L. Greninger: University of Washington
Daniel Stone: Fred Hutchinson Cancer Research Center
Keith R. Jerome: Fred Hutchinson Cancer Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract We evaluate gene editing of HSV in a well-established mouse model, using adeno-associated virus (AAV)-delivered meganucleases, as a potentially curative approach to treat latent HSV infection. Here we show that AAV-delivered meganucleases, but not CRISPR/Cas9, mediate highly efficient gene editing of HSV, eliminating over 90% of latent virus from superior cervical ganglia. Single-cell RNA sequencing demonstrates that both HSV and individual AAV serotypes are non-randomly distributed among neuronal subsets in ganglia, implying that improved delivery to all neuronal subsets may lead to even more complete elimination of HSV. As predicted, delivery of meganucleases using a triple AAV serotype combination results in the greatest decrease in ganglionic HSV loads. The levels of HSV elimination observed in these studies, if translated to humans, would likely significantly reduce HSV reactivation, shedding, and lesions. Further optimization of meganuclease delivery and activity is likely possible, and may offer a pathway to a cure for HSV infection.

Date: 2020
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DOI: 10.1038/s41467-020-17936-5

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