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EIAV encodes an accessory protein that antagonizes the host restriction factor equine tetherin.
Abstract: Equine infectious anemia virus (EIAV) is an important model for the study of pathogenesis in lentiviruses. Studies of viral genome organization and replication mechanisms are fundamental to the understanding of virus pathogenicity. In this study, we identified an unique transcript from EIAV in vivo and in vitro by Sanger sequencing and Northern blotting. The transcript contains a complete open reading frame and has length 369 nt. We named the protein encoded by this transcript S4 and demonstrated its expression in EIAV-infected cells. An S4-deficient EIAV infectious clone displayed obviously impaired virion release and attenuated virus replication in vitro, demonstrating that S4 plays a role in the release step of EIAV. The host restriction factor tetherin has broad-spectrum antiviral activity and prevents the release of a wide range of enveloped viruses, including lentiviruses. Here, we demonstrated that S4 enhances the release of the EIAV-like particle by counteracting the equine tetherin (eqTHN). S4 interacts with the eqTHN and sequesters it within intracellular membrane compartments, attenuating eqTHN expression on the cell surface and thereby disrupting its antiviral activity. Further investigation revealed that S4 retains eqTHN in the endoplasmic reticulum and trans-Golgi network through impacting its anterograde transport to the cell surface and may interfere with the posttranslational modification of this membrane protein. Collectively, our findings uncover an accessory protein, S4, of EIAV and reveal its ability to promote virion release by antagonizing the antiviral activity of the host restriction factor tetherin.
Publication Date: 2025-06-23 PubMed ID: 40549908PubMed Central: PMC12232724DOI: 10.1073/pnas.2413703122Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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EIAV produces an accessory protein called S4 that helps the virus overcome the host’s antiviral defense by blocking the action of equine tetherin, a protein that normally prevents virus particles from leaving infected cells. This study identifies and characterizes the S4 protein and shows how it supports virus release and replication.
Background and Significance
- Equine infectious anemia virus (EIAV) is a lentivirus used as a model for understanding virus pathogenesis.
- Understanding viral genome structure and replication contributes to insight into how viruses cause disease.
- Host organisms have restriction factors like tetherin that block the release of enveloped viruses to limit infection.
- Equine tetherin (eqTHN) is a host antiviral protein that inhibits release of EIAV particles from infected cells.
Discovery of the S4 Transcript and Protein
- Researchers identified a unique EIAV transcript, 369 nucleotides in length, via Sanger sequencing and Northern blotting.
- This transcript contains a complete open reading frame encoding a previously unknown protein they named S4.
- S4 expression was confirmed in cells infected by EIAV, showing it is produced during infection.
Functional Role of S4 in Virus Replication
- A viral clone lacking the S4 gene showed impaired release of virus particles and reduced replication efficiency in vitro.
- This demonstrates that S4 is important specifically at the virion release step of the viral life cycle.
Interaction Between S4 and Equine Tetherin
- S4 was found to counteract the antiviral function of eqTHN, enhancing release of EIAV-like particles.
- S4 physically interacts with eqTHN protein.
- It sequesters eqTHN within intracellular membrane compartments, preventing eqTHN from reaching the cell surface.
- By reducing eqTHN on the cell surface, S4 disrupts eqTHN’s ability to block viral particle release.
Mechanism of S4-mediated Tetherin Antagonism
- S4 retains eqTHN in the endoplasmic reticulum and trans-Golgi network compartments.
- This retention inhibits the normal transport of eqTHN to the plasma membrane.
- S4 may also affect posttranslational modifications of eqTHN, potentially impacting its stability or function.
Conclusions and Implications
- The study uncovers S4 as a novel EIAV accessory protein with a key role in overcoming host defense.
- S4 promotes virion release by antagonizing equine tetherin’s antiviral activity, facilitating virus spread.
- These findings expand knowledge of EIAV biology and host-virus interactions relevant to lentiviruses broadly.
- Understanding how viruses evade tetherin may inform development of antiviral therapies or vaccines.
Cite This Article
APA
Bai B, Zhang X, Zhang M, Ma W, Li J, Zhang H, Na L, Guo X, Lin Y, Wang XF, Wang X.
(2025).
EIAV encodes an accessory protein that antagonizes the host restriction factor equine tetherin.
Proc Natl Acad Sci U S A, 122(26), e2413703122.
https://doi.org/10.1073/pnas.2413703122 Publication
Researcher Affiliations
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Equine Infectious Diseases and Lentiviruses Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
- Institute of Western Agriculture, The Chinese Academy of Agricultural Sciences, Changji 831100, China.
MeSH Terms
- Infectious Anemia Virus, Equine / genetics
- Infectious Anemia Virus, Equine / metabolism
- Infectious Anemia Virus, Equine / physiology
- Animals
- Horses
- Bone Marrow Stromal Antigen 2 / metabolism
- Bone Marrow Stromal Antigen 2 / genetics
- Virus Replication
- Humans
- Equine Infectious Anemia / virology
- Equine Infectious Anemia / metabolism
- Virion / metabolism
- Viral Regulatory and Accessory Proteins / genetics
- Viral Regulatory and Accessory Proteins / metabolism
Grant Funding
- 32172831; 31672578 / MOST | National Natural Science Foundation of China (NSFC)
- 32170169 / MOST | National Natural Science Foundation of China (NSFC)
Conflict of Interest Statement
Competing interests statement:The authors declare no competing interest.
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Citations
This article has been cited 1 times.- Chen Y, Wu L, Fan W, Wang Y, Li J, Zhang X, Zhang Z, Li Y, Wang S, Liu Y, Qi X, Zhang Y, Cui H, Duan Y, Gao Y. MARCH2 inhibits avian leukosis virus replication by targeting gp85 for ubiquitination and degradation.. J Virol 2025 Dec 23;99(12):e0161625.
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