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Gene editing and elimination of latent herpes simplex virus in vivo

Author

Listed:
  • 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
    University of Washington)

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.

Suggested Citation

  • 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 & Harsha, 2020. "Gene editing and elimination of latent herpes simplex virus in vivo," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17936-5
    DOI: 10.1038/s41467-020-17936-5
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    Cited by:

    1. 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 & Martin, 2024. "Viral gene drive spread during herpes simplex virus 1 infection in mice," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Yidan Wang & Ying Xu & Chee Wah Tan & Longliang Qiao & Wan Ni Chia & Hongyi Zhang & Qin Huang & Zhenqiang Deng & Ziwei Wang & Xi Wang & Xurui Shen & Canyu Liu & Rongjuan Pei & Yuanxiao Liu & Shuai Xue, 2022. "Engineering antiviral immune-like systems for autonomous virus detection and inhibition in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Martine Aubert & Anoria K. Haick & Daniel E. Strongin & Lindsay M. Klouser & Michelle A. Loprieno & Laurence Stensland & Tracy K. Santo & Meei-Li Huang & Ollivier Hyrien & Daniel Stone & Keith R. Jero, 2024. "Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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