In a new study, researchers from the University of Oxford, the University of Cambridge, and the Pirbright Institute in the UK have discovered a novel therapeutic approach to investigating how poxviruses evade the natural defense mechanisms of human cells. This approach could potentially offer more enduring benefits compared to current treatment methods. Earlier, they had revealed how poxviruses hijack a cellular protein to evade the host cell defenses, enabling efficient replication and spread. The findings were published online on August 9, 2023, in the journal Nature under the title “TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6”.
Existing immunosuppressive drugs or drugs used for treating other viral infections target this specific cellular protein. In this new research, the authors discovered that these drugs also restrict the replication and spread of poxviruses. This therapeutic approach doesn’t directly target the poxviruses, which implies that these viruses might find it more difficult to evolve resistance. As this hijacking mechanism is common across many poxviruses, these drugs could effectively treat a range of diseases, including monkeypox (caused by a poxvirus called monkeypox virus) and smallpox (caused by a poxvirus known as variola virus).
Although smallpox was eradicated as a disease in 1979, the causative agent, the variola virus, is still preserved in two highly secure laboratories—one in the United States and another in Russia. Due to the potential for bioterrorism using the variola virus, a drug called tecovirimat has been approved for treating smallpox.
Monkeypox, caused by the monkeypox virus, is still prevalent, with infection numbers declining in the UK but still present, especially in London and various other countries. Last year, tecovirimat was used to treat severe cases of monkeypox, leading to the emergence of multiple drug-resistant strains of monkeypox virus.
Professor Geoffrey L. Smith, co-senior author of the paper and affiliated with the Department of Pathology at the University of Cambridge, the Dunn School of Pathology at the University of Oxford, and the Pirbright Institute, stated, “The drugs we’ve identified could be more enduring than current methods for treating monkeypox—and we hope these drugs will also work against a range of other poxviruses, including those that cause smallpox.”
Once a poxvirus infects a host cell, it must withstand attacks from cellular proteins that restrict virus replication and spread. These researchers found that a specific cellular protein called TRIM5α restricts virus growth, while another protein called cyclophilin A (CypA) prevents TRIM5α from performing its function. Existing drugs target CypA, making poxviruses more sensitive to TRIM5α.
Smith noted, “There are already several drugs targeting CypA, and because many of these have been through clinical trials, we’re not starting from scratch but are repurposing existing drugs, which is much faster.”
Many other poxviruses also affect animals. For instance, the global outbreak of lumpy skin disease is currently impacting cattle and can be fatal.
Smith added, “Our findings were completely unexpected. We started this study to understand the basic science of how poxviruses evade host defenses, and we never anticipated that this might lead to drugs for treating monkeypox and other poxviruses.”
Professor Guy Poppy, Interim CEO of the Biotechnology and Biological Sciences Research Council (BBSRC), said, “The establishment of the National Monkeypox Research Alliance responds to an urgent need for the UK to be prepared to respond to new disease threats from the monkeypox virus. It’s crucial that public funders and policymakers can take swift, coordinated action to support rapid scientific responses.”
The project began with a simple observation that infection with the vaccinia virus leads to a decrease in levels of TRIM5α in human cells. To uncover the reason behind this, the researchers designed human cells lacking TRIM5α and found that the virus replicated and spread more effectively in these cells. This indicated that TRIM5α possesses antiviral activity.
Subsequently, they identified the vaccinia virus protein targeted by TRIM5α. They also discovered that the virus employs two defense mechanisms against TRIM5α: firstly, it utilizes another cellular protein, CypA, to block TRIM5α’s antiviral activity; secondly, it generates a viral protein, C6, to induce the degradation of TRIM5α. Thus, therapies targeting the degradation of viral proteins may offer new avenues for treating poxviruses.