Viral gene drive spread during herpes simplex virus 1 infection in mice

Marius Walter (), Anoria K. Haick, Rebeccah Riley, Paola A. Massa, Daniel E. Strongin, Lindsay M. Klouser, Michelle A. Loprieno, Laurence Stensland, Tracy K. Santo, Pavitra Roychoudhury, Martine Aubert, Matthew P. Taylor, Keith R. Jerome () and Eric Verdin ()
Additional contact information
Marius Walter: Fred Hutch Cancer Center
Anoria K. Haick: Fred Hutch Cancer Center
Rebeccah Riley: Buck Institute for Research on Aging
Paola A. Massa: Fred Hutch Cancer Center
Daniel E. Strongin: University of Washington
Lindsay M. Klouser: Fred Hutch Cancer Center
Michelle A. Loprieno: Fred Hutch Cancer Center
Laurence Stensland: University of Washington
Tracy K. Santo: University of Washington
Pavitra Roychoudhury: Fred Hutch Cancer Center
Martine Aubert: Fred Hutch Cancer Center
Matthew P. Taylor: Montana State University
Keith R. Jerome: Fred Hutch Cancer Center
Eric Verdin: Buck Institute for Research on Aging

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Gene drives are genetic modifications designed to propagate efficiently through a population. Most applications rely on homologous recombination during sexual reproduction in diploid organisms such as insects, but we recently developed a gene drive in herpesviruses that relies on co-infection of cells by wild-type and engineered viruses. Here, we report on a viral gene drive against human herpes simplex virus 1 (HSV-1) and show that it propagates efficiently in cell culture and during HSV-1 infection in mice. We describe high levels of co-infection and gene drive-mediated recombination in neuronal tissues during herpes encephalitis as the infection progresses from the site of inoculation to the peripheral and central nervous systems. In addition, we show evidence that a superinfecting gene drive virus could recombine with wild-type viruses during latent infection. These findings indicate that HSV-1 achieves high rates of co-infection and recombination during viral infection, a phenomenon that is currently underappreciated. Overall, this study shows that a viral gene drive could spread in vivo during HSV-1 infection, paving the way toward therapeutic applications.

Date: 2024
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DOI: 10.1038/s41467-024-52395-2

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