Limitations of acyclovir and identification of potent HSV antivirals using 3D bioprinted human skin equivalents
Herpes simplex virus (HSV) infection poses global public health concerns with lifelong impacts. Acyclovir, the standard therapy, has limited efficacy in preventing subclinical shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. Here we show that acyclovir is significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. Using 3D bioprinted human skin equivalents (HSEs) in a 96-well plate format, we have screened 738 compounds with broad targets and mechanisms of action, identifying potent antivirals, including 23 known or experimental HSV treatments. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways display similar potency across cell types and donor sources in both 2D and 3D models. The reduced potency in keratinocytes may explain acyclovir's limited clinical efficacy. Our 3D bioprinted HSE assay platform enables the integration of patient-derived cells early in drug development and offers a physiologically relevant approach for HSV drug discovery.
Authors
- Marc Ferrer (ORCID: https://orcid.org/0000-0003-4569-9137)
- A.M. Jones
- Zina Itkin (ORCID: https://orcid.org/0000-0003-1686-1326)
- S. Tori Ellison (ORCID: https://orcid.org/0000-0002-5606-1668)
- Anna Wald (ORCID: https://orcid.org/0000-0003-3486-6438)
- Paige Derr
- Lawrence Corey (ORCID: https://orcid.org/0000-0002-2179-2436)
- Youyi Fong (ORCID: https://orcid.org/0000-0002-4230-6863)
- Christine Johnston (ORCID: https://orcid.org/0000-0002-3073-0843)
- Jia Zhu (ORCID: https://orcid.org/0000-0002-8676-5105)
- Kristy Derr
- Min Shen (ORCID: https://orcid.org/0000-0002-8218-0433)
- Ian Hayman (ORCID: https://orcid.org/0000-0001-7712-2872)
- Shayne Frebert
- Wendy Olson
Institutions
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Infectious Disease Research Institute (US)
- California Institute for Regenerative Medicine (US)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- National Center for Advancing Translational Sciences (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-16
- DOI
- https://doi.org/10.1038/s41467-025-64245-w
- Citations
- 3
- Primary Topic
- Herpesvirus Infections and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.06
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Center for Advancing Translational Sciences