학술논문
Gene editing and elimination of latent herpes simplex virus in vivo
Document Type
article
Author
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. De Silva Feelixge; Roman Galetto; Philippe Duchateau; Alexander L. Greninger; Daniel Stone; Keith R. Jerome
Source
Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020)
Subject
Language
English
ISSN
2041-1723
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.