Scientists have discovered how poxviruses, including those causing smallpox and mpox (the disease caused by the monkeypox virus) evade natural defences in living cells. They have also realised that drugs to stop them doing this are already available.
This follows their discovery of how poxviruses exploit a cellular protein to evade the host cell defences and thereby replicate and spread effectively.
Existing drugs developed to be immunosuppressive or treat other viral infections target this cellular protein. The team found that these drugs can also restrict the replication and spread of poxviruses.
This approach to treatment, in which the drug does not directly target the virus, means that it will be much more difficult for the virus to evolve drug resistance.
Because this hijacking mechanism is the same across many poxviruses, the drugs will be effective in treating a range of diseases such as mpox and smallpox.
Although smallpox was eradicated as a disease in 1979, the virus that causes it, variola, is still held in two high security labs in the US and Russia.
The threat of variola virus being used in bioterrorism has led to a drug, tecovirimat, being licensed to treat smallpox.
There is an ongoing epidemic of mpox, and while the number of infections has dropped in the UK it is still present, particularly in London and many other nations.
Tecovirimat has been used to treat severe cases of mpox over the last year, but this has resulted in the emergence of multiple drug resistant strains of the monkeypox virus.
More durable treatments
Professor Geoffrey L Smith, who conducted the work in the Department of Pathology at the University of Cambridge, the Dunn School of Pathology at the University of Oxford and The Pirbright Institute, said:
The drugs we identified may be more durable than the current treatment for monkeypox. We expect they will also be effective against a range of other poxviruses, including the one that causes smallpox.
Restricting virus replication and spread
Once a poxvirus infects a host cell, it has to defend itself from attack by cellular proteins that would restrict virus replication and spread.
Researchers identified a specific cell protein called TRIM5α that restricts virus growth and another called Cyclophilin A that prevents TRIM5α doing so. Existing drugs target Cyclophilin A, thus making the virus more sensitive to TRIM5α.
Professor Smith said:
There are various drugs that target Cyclophilin A. Because many of them have gone through clinical trials, we wouldn’t be starting from scratch but repurposing existing drugs, which is much quicker.
Many other poxviruses affect animals. For example, a global pandemic of lumpy skin disease is currently affecting cattle and can be fatal.
Basic science is key
Professor Smith said:
Our results were completely unexpected. We started the research because we’re interested in understanding the basic science of how poxviruses evade host defences.
We had absolutely no idea this might lead to drugs to treat monkeypox virus and other poxviruses.
Rapid response to emerging threats
In October 2022, the Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC) invested £2 million in a new UK research consortium to tackle the monkeypox outbreak.
Professor Guy Poppy, Interim Executive Chair at BBSRC, said:
The national monkeypox consortium was borne out of an urgent need for the UK to respond to an emerging threat of disease caused by this virus. It is critical that public funders and policy makers are able to act with agility and coordination to support a swift scientific response.
Taking a One Health approach, the rapid response by BBSRC and MRC, in collaboration with policy makers via the UKRI Tackling Infections strategic theme, enabled leading researchers from across the UK to pool their expertise and deliver impactive results at pace.
The science behind the discovery
The project started with the simple observation that vaccinia virus infection causes a reduction in the level of TRIM5α in human cells.
To find out why, the team engineered human cells to lack TRIM5α and found that in these cells the virus replicated and spread better. This shows that TRIM5α has anti-viral activity.
Next, they identified the vaccinia virus protein that TRIM5α targets. They also discovered that the virus has two defences against attack by TRIM5:
- first, it exploits another cellular protein, Cyclophilin A, to block the antiviral activity of TRIM5α
- second, it makes a protein called C6 that induces destruction of TRIM5α
Existing drugs target Cyclophilin A. When the team tested a series of these drugs against a range of poxviruses, including monkeypox, they had antiviral effects in all cases. The drugs work by making the virus more sensitive to TRIM5α.
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