Poxviruses are large, enveloped, double-stranded DNA viruses that are responsible for a range of diseases in humans and animals. Smallpox remains the first and only viral infection to be eradicated in humans following a successful vaccination campaign. However, several other poxviruses pose a high health risk, including the recent resurgence of monkeypox. The drug Tecovirimat has been used to treat severe cases of monkeypox, but reports of drug-resistance are already becoming more frequent suggesting that other drug treatments are required.
Professor Geoffrey L Smith (CAMS Oxford Institute Principal Investigator & Professor at Sir William Dunn School), who has spent over 40 years studying poxvirus biology, has led a team of researchers from across the University of Cambridge, the University of Oxford & The Pirbright Institute to understand how poxviruses evade host defences. Through analysis of the proteome of infected cells they identified that TRIM5α, an innate restriction factor, was down-regulated during poxvirus infection.
TRIM5α is already known to restrict retroviruses by preventing uncoating of the viral capsid. In this study, the researchers showed that when TRIM5α was absent, the poxvirus vaccinia virus was able to replicate and infect more cells that occurred in the presence of TRIM5α. Vaccinia virus was able to antagonise TRIM5α expression by inducing its proteasome-dependent degradation and by recruiting cyclophilin A (CypA), which binds to the viral capsid protein that TRIM5α would target, thereby preventing it's restriction.
CypA is a target of existing drugs, such as cyclosporine A and several non-immunosuppressive derivatives. Cyclosporine A is used primarily for the treatment of autoimmune conditions such as rheumatoid arthritis or Crohn's disease and in organ transplants to prevent rejection. Notably, it was shown that these drugs were able to reduce the replication and spread of several different orthopoxviruses, including monkeypox, camelpox, cowpox and vaccinia viruses. This is of particular importance because these drugs target a cellular protein making it difficult for the virus to evolve drug resistance.
The interactions between the cellular proteins TRIM5α and CypA, and the viral proteins C6 and L3 that are highlighted in this study, were shown to be conserved across a range of orthopoxpox viruses, including variola virus, suggesting that the CypA-targeting drugs could act against a broad spectrum of poxvirus infections. Despite the potential clinical applications, Prof Smith emphasises that this project started off as a basic science story – one trying to understand the underlying mechanisms of host defences against viruses and viral evasion of these defences. These unforeseen results simply emphasise the importance of investing in basic science research.
Research article: Zhao et al. (2023) TRIM5α restricts poxviruses and is antagonized by CypA and viral protein C6. Nature. https://doi.org/10.1038/s41586-023-06401-0