For millions of years viruses have been evolving ways to outsmart our immune system so they can replicate inside our bodies and spread. In the process many cause infectious diseases, ranging from the common cold and influenza to hepatitis and AIDS. Now, by gaining a greater insight into their complex mechanisms, virologists are manipulating viruses to work for, rather than against, us.

“We’re trying to understand how our immune system works – how it responds to and fights pathogens, particularly viruses,” said Professor Geoffrey L. Smith, Head of the University’s Department of Pathology. “If you want to study the immune system, you study the pathogens. Viruses have known how our immune system works for millions of years, and have developed many methods to overcome it. But we are only now discovering these secrets.”

Smith leads a team of virologists focused on vaccinia virus, from which vaccination gets its name, and the one used to wipe out smallpox. “The virus has about 200 genes, and amazingly about half of these code for proteins that block the host immune response. This is a fantastic resource for understanding our immune system,” said Smith.

Building better vaccines

“The smallpox vaccine was very successful – indeed it was the only vaccine that has ever eradicated a human disease,” said Smith. “By generating an immune response it provided protection against devastating illness. But it was imperfect in terms of safety, causing various complications and, in rare cases, death. If we’re going to reuse vaccinia for other vaccines, we need to improve its safety.”

Working in Bernard Moss’s laboratory in the USA in the 1980s, Smith and fellow postdoc Michael Mackett developed methods to genetically engineer vaccinia so that a gene taken from another organism could be inserted into it. The aim was to make vaccinia produce foreign antigens – molecules against which antibodies are produced. “Now we can insert the gene encoding the desired antigen from any pathogen – bacteria, virus, or parasite – into vaccinia, and get vaccinia to express the antigen and present it to the host immune system. This initiates an immune response, making the host immunised against the pathogen from which that gene was derived.”

Vaccinia is now being developed into a variety of vaccines, which are undergoing clinical trials against diseases including AIDS and tuberculosis. “It’s a generic platform that we can manipulate and target against different diseases,” said Smith. “But we want to end up with a vaccine that is safer and more potent. The platform can be improved by removing genes that enable the virus to block our immune system, if we can work out what these are.”

Detecting infection

Smith’s team is exploiting vaccinia to understand the complexities of our immune system. Finding the molecular signals that tell a cell it is infected has been a goal of immunologists for decades. In an article published in the new online journal eLife in December, Dr Brian Ferguson, recently appointed to University Lecturer in the Department of Pathology and a former member of Smith’s lab, describes a newly discovered mechanism by which the immune system detects invading DNA viruses.

“We have been looking at how the body knows it’s infected by a virus,” said Ferguson. “To fight off an invading virus, we have to know it’s there. We have systems in all our cells to sense invaders and to respond by producing danger signals. We’ve discovered that an already well-characterised protein called DNA-protein kinase (DNA-PK) acts as the initial sensor to detect infection.”

In its role as a ‘pattern recognition receptor’, DNA-PK senses when viral DNA is present in the body and sounds the alarm, telling the body to mount a rapid inflammatory response. “The DNA-PK works by binding to the foreign DNA it detects in the cell, and initiating a sequence of signalling events culminating in the production of molecules that amplify the body’s response to the infection,” added Ferguson.

“We’ve also discovered how vaccinia inhibits the immune system by interfering with DNA-PK,” said Smith. A parallel investigation by PhD student Nicholas Peters, conducted in Smith’s laboratory while at its former Imperial College London base, studied a protein made by vaccinia called C16. “We knew if we removed the gene coding for C16, vaccinia became less virulent,” said Smith. “Nick’s project was to understand how this worked. He tagged the C16 protein with a marker, introduced it into cells, and captured the molecules C16 bound to in the cells.”

“Remarkably, C16 bound to two proteins that were part of the same DNA-PK complex that Brian had found was sensing virus invasion,” said Smith. “This showed the additional biological significance of DNA-PK in restricting virus replication, because the virus has evolved a mechanism to prevent the triggering of an immune response. This explained why removal of C16 from vaccinia made it less virulent”.

“Understanding the ways viruses have chosen to block our immune response is also useful because it shows us how to develop anti-inflammatory therapeutic agents,” said Smith. “Diseases caused by excessive inflammation like rheumatoid arthritis derive from the inflammatory response not being properly regulated. Pathways activated by sensors like DNA-PK may be switched on all the time. Targeting such pathways would regulate the inflammatory response.”

Knowledge is power

While our understanding of viruses grows, the emergence of new strains poses an ongoing threat to animal and human health. “It’s our own fault for creating niches that viruses can occupy,” said Smith. When humans existed at low population densities, viruses like variola (the cause of smallpox) and measles couldn’t persist in man. They induced long-lasting immunity in their hosts and, with insufficient numbers of non-immune hosts to infect, they died out. But once population densities increased, these viruses could constantly be passed to new hosts and great epidemics ensued. Smallpox killed 300 million people in the 20th century alone.

“Viruses are constantly evolving new ways to evade our immune system, and we need to understand their fundamental infection mechanisms, and ultimately how they kill people,” said Ferguson. “It’s an arms race that has been going on for millions of years. The human body is evolving new ways of detecting and fighting viruses, but at the same time the virus is evolving new ways to inhibit those mechanisms.”

Advanced gene-sequencing technologies are giving immunologists a much clearer understanding of both human and viral DNA. “Sequencing an entire viral genome used to take years. With new technology we can do it in days,” said Ferguson. “This will help us better understand how they mutate and evolve. And sequencing our own genome will help us to find out why some people are more susceptible to disease than others, and how different people will respond to a vaccine. These new technologies are an extremely powerful tool to understand the interactions between the virus and the human body.”

“A major drive is to develop vaccines based on DNA or DNA-containing viruses that express antigens specific to different pathogens,” said Ferguson. “If we can contribute to a better understanding of how existing vaccines work, we will be able to improve them. Our long-term goal is to make better vaccines and understand how to develop anti-inflammatory therapeutics, learning from the mechanisms viruses themselves have evolved.”