Restraint of Powassan virus replication by TRIM5α facilitates viral avoidance of antiviral immunity
12 affiliations
- 1Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT USA
- 2Present Address: Dispatch Biotherapeutics, Philadelphia, PA USA
- 3Present Address: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO USA
- 4Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT USA
- 5Molecular Parasitology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD USA
- 6TSE/Prion Biochemistry Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT USA
- 7Present Address: Boehringer Ingelheim, Biberach, Germany
- 8Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT USA
- 9Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD USA
- 10Reserch Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT USA
- 11School of Biological Sciences, University of Adelaide, Adelaide, SA Australia
- 12Present Address: College of Medicine and Public Health, Flinders University, Adelaide, SA Australia
Abstract
TRIpartite Motif (TRIM) protein 5 alpha (TRIM5α) is a well-characterized cellular inhibitor of lentivirus replication that limits transmission of related viruses between primates. We previously reported that TRIM5α derived from humans and rhesus macaques inhibits replication of orthoflaviviruses belonging to the tick-borne encephalitis virus (TBEV) serocomplex, including TBEV, Kyasanur forest disease virus and Langat virus (LGTV), but interestingly not the tick-borne Powassan virus (POWV). To further characterize the primate TRIM5α and orthoflavivirus interface, we screened TRIM5α variants from representative old- and new-world primates for restriction capacity. TRIM5α from old-world African green monkey, De Brazza’s monkey and chimpanzee demonstrated virus-specific restriction of tick-borne orthoflaviviruses. Efforts to determine why TRIM5α fails to inhibit POWV revealed that our lab stock had acquired a non-synonymous mutation in NS3 that, when introduced into a POWV molecular clone, facilitated virus replication in the presence of all inhibitory primate TRIM5α proteins. Infection of human dendritic cells with TRIM5α-resistant POWV resulted in high early replication and strong induction of interferon responses that limited replication compared with the wild-type virus. Thus, primate TRIM5α functions as a potent cellular barrier to infection with tick-borne orthoflaviviruses that restrains replication to a level that may help avoid early innate immune recognition.
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BibTeX
@article{broeckel2026restraint,
title = {{Restraint of Powassan virus replication by TRIM5α facilitates viral avoidance of antiviral immunity}},
author = {Rebecca M. Broeckel and Emily A. Fitzmeyer and Eva Chebishev and Jeffrey G. Shannon and Byron Shue and Adam Hage and Stephanie Spada and Efrosini Artikis and Abhilash I. Chiramel and Kristin L. McNally and Charles L. Larson and Maarit von Kutzleben and Shelly J. Robertson and Danielle K. Offerdahl and Hilary A. Lakin and Marshall E. Bloom and Skyler Kuhn and Vinod Nair and Nicholas S. Eyre and Michael R. Beard and Michael E. Grigg and Fadila Bouamr and Sonja M. Best},
journal = {Communications Biology},
year = {2026},
month = jul,
doi = {10.1038/s42003-026-10613-1},
url = {https://doi.org/10.1038/s42003-026-10613-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Restraint of Powassan virus replication by TRIM5α facilitates viral avoidance of antiviral immunity
AU - Rebecca M. Broeckel
AU - Emily A. Fitzmeyer
AU - Eva Chebishev
AU - Jeffrey G. Shannon
AU - Byron Shue
AU - Adam Hage
AU - Stephanie Spada
AU - Efrosini Artikis
AU - Abhilash I. Chiramel
AU - Kristin L. McNally
AU - Charles L. Larson
AU - Maarit von Kutzleben
AU - Shelly J. Robertson
AU - Danielle K. Offerdahl
AU - Hilary A. Lakin
AU - Marshall E. Bloom
AU - Skyler Kuhn
AU - Vinod Nair
AU - Nicholas S. Eyre
AU - Michael R. Beard
AU - Michael E. Grigg
AU - Fadila Bouamr
AU - Sonja M. Best
PY - 2026
DA - 2026/07/07
JO - Communications Biology
DO - 10.1038/s42003-026-10613-1
UR - https://doi.org/10.1038/s42003-026-10613-1
AB - TRIpartite Motif (TRIM) protein 5 alpha (TRIM5α) is a well-characterized cellular inhibitor of lentivirus replication that limits transmission of related viruses between primates. We previously reported that TRIM5α derived from humans and rhesus macaques inhibits replication of orthoflaviviruses belonging to the tick-borne encephalitis virus (TBEV) serocomplex, including TBEV, Kyasanur forest disease virus and Langat virus (LGTV), but interestingly not the tick-borne Powassan virus (POWV). To further characterize the primate TRIM5α and orthoflavivirus interface, we screened TRIM5α variants from representative old- and new-world primates for restriction capacity. TRIM5α from old-world African green monkey, De Brazza’s monkey and chimpanzee demonstrated virus-specific restriction of tick-borne orthoflaviviruses. Efforts to determine why TRIM5α fails to inhibit POWV revealed that our lab stock had acquired a non-synonymous mutation in NS3 that, when introduced into a POWV molecular clone, facilitated virus replication in the presence of all inhibitory primate TRIM5α proteins. Infection of human dendritic cells with TRIM5α-resistant POWV resulted in high early replication and strong induction of interferon responses that limited replication compared with the wild-type virus. Thus, primate TRIM5α functions as a potent cellular barrier to infection with tick-borne orthoflaviviruses that restrains replication to a level that may help avoid early innate immune recognition.
SN - 2399-3642
ER -