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Restraint of Powassan virus replication by TRIM5α facilitates viral avoidance of antiviral immunity
Rebecca M Broeckel1,2, Emily A Fitzmeyer1,3, Eva Chebishev1
1Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
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.
Insights
Primate TRIM5α protein restricts tick-borne orthoflaviviruses, except for a Powassan virus (POWV) variant with an NS3 mutation. This restriction limits viral replication, potentially preventing early innate immune detection.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- TRIpartite Motif protein 5 alpha (TRIM5α) inhibits lentivirus replication.
- Primate TRIM5α restricts some orthoflaviviruses, but not Powassan virus (POWV).
Purpose of the Study:
- Characterize the interaction between primate TRIM5α and orthoflaviviruses.
- Identify factors influencing TRIM5α restriction of tick-borne orthoflaviviruses.
Main Methods:
- Screened TRIM5α variants from various primates for restriction capacity against orthoflaviviruses.
- Introduced a specific mutation into a POWV molecular clone to assess its impact on TRIM5α restriction.
- Infected human dendritic cells with wild-type and mutant POWV.
Main Results:
- TRIM5α from African green monkey, De Brazza's monkey, and chimpanzee restricted tick-borne orthoflaviviruses.
- A mutation in POWV NS3 enabled replication despite TRIM5α inhibition.
- TRIM5α-resistant POWV showed high early replication and induced strong interferon responses.
Conclusions:
- Primate TRIM5α acts as a cellular barrier against tick-borne orthoflaviviruses.
- TRIM5α limits viral replication, potentially influencing innate immune recognition.
- POWV's NS3 mutation confers resistance to primate TRIM5α restriction.
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