Treatment for Poxviruses Already Exists in Licensed Drugs

Scientists exploring how poxviruses circumvent natural defenses in human cells have discovered a novel therapeutic strategy that may be more effective than current treatments.

This follows their discovery of how poxviruses employ a cellular protein to avoid host cell defenses and effectively multiply and propagate.

Existing medications designed to inhibit the immune system or cure other viral infections target this cellular protein. The researchers discovered that these medications can also limit the multiplication and spread of poxviruses.

This treatment strategy, in which the antibiotic does not directly target the virus, makes it considerably more difficult for the virus to develop drug resistance.

Because the hijacking method is shared by numerous poxviruses, the medications will be useful in treating a variety of illnesses, including mpox and smallpox.

The findings were published in the journal Nature.

Despite the fact that smallpox has been declared eradicated as a disease since 1979, the virus that causes it, variola, is still housed in two high-security laboratories, one in the United States and one in Russia. The possibility of variola virus being utilized in bioterrorism has resulted in the approval of tecovirimat as a smallpox treatment.

Although the incidence of illnesses in the UK has decreased, mpox (produced by the monkeypox virus) is still widespread, particularly in London and many other countries.

Over the last year, tecovirimat has been used to treat severe cases of mpox, but this has caused in the establishment of various drug-resistant strains of the monkeypox virus.

“The drugs we identified may be more durable than the current treatment for monkeypox – and we expect will also be effective against a range of other poxviruses including the one that causes smallpox,” said Professor Geoffrey L. Smith, who conducted the work in the Department of Pathology at the University of Cambridge, the Dunn School of Pathology, University of Oxford and the Pirbright Institute.

Once a poxvirus penetrates a host cell, it must protect itself against cellular proteins that would otherwise prevent virus reproduction and spread. Researchers discovered TRIM5, a cell protein that inhibits viral multiplication, and cyclophilin A, a cell protein that stops TRIM5 from doing so. Existing medications target cyclophilin A, making the virus more susceptible to TRIM5.

“There are various drugs that target cyclophilin A, and because many of them have gone through clinical trials we wouldn’t be starting from scratch but repurposing existing drugs, which is much quicker,” said Smith.

Many additional poxviruses have an impact on animals; for example, a global pandemic of ‘Lumpy skin disease’ is currently afflicting cattle and can be lethal.

Smith added: “Our results were completely unexpected. We started the research because we’re interested in understanding the basic science of how poxviruses evade host defences and we had absolutely no idea this might lead to drugs to treat monkeypox virus and other poxviruses.”

Professor Guy Poppy, Interim Executive Chair at the Biotechnology and Biological Sciences Research Council (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 the Medical Research Council (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 that led to the discovery

The experiment began with the simple observation that vaccinia virus infection caused a decrease in TRIM5 levels in human cells. To figure out why, the researchers modified human cells to lack TRIM5 and discovered that the virus multiplied and disseminated more effectively in these cells. This demonstrates that TRIM5 has antiviral action.

They then discovered the vaccinia virus protein that TRIM5 targets. They also revealed that the virus has two defenses against TRIM5 attack: first, it uses another cellular protein, cyclophilin A, to prevent TRIM5’s antiviral function, and second, it produces a protein, C6, that causes TRIM5 degradation.

Existing medications target cyclophilin A. When the researchers tested a number of these medications against a variety of poxviruses, including monkeypox, they found that they all showed antiviral properties. The medications act by increasing the virus’s sensitivity to TRIM5.

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