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The group of proteins called interferons are manufactured and released by host cells in response to the presence of viruses and other pathogens. Their job is to disrupt the way the pathogen works in the body like a resistance movement fighting an invading army. They also activate the body’s natural killer (NK) cells that are there to kill off pathogens, and help to make the virus more visible and open to attack by the host immune system. There are several genes that are important to the proper functioning of interferons. These antiviral genes and their ability to destroy how viruses work is the primary research interest of Dr Nigel Stevenson, Assistant Professor of Intracellular Immunology at Trinity College, Dublin.
Dr Stevenson’s research group at Trinity is interested in everything that happens within cells of the immune system. He explained that they are particularly looking at signalling pathways inside cells. These are the signals or messages that are constantly going back and forth inside an immune cell. The signals work like molecular dominoes in a chain, said Dr Stevenson, and when the endpoint in the signal chain is reached there is expression or activation of hundreds of antiviral genes that make it impossible for viruses to live in cells.
There have been significant changes in the treatment of HCV since Dr Stevenson began his research on the virus in 2008
Dr Stevenson and his team, which includes three medical doctors (two working on a PhD and the other on an MD), are interested in understanding how these signalling chains or pathways get rid of viruses, and how viruses target these pathways and try to disrupt their proper working. The team has found that some viruses are indeed capable of targeting and disrupting the pathways inside cells. The team has been working on HIV, hepatitis C virus (HCV), respiratory syncytial virus (RSV), severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS) and found that HCV and RSV can target the all-important signalling pathways inside host immune cells.
In the eternal battle between viruses and immune cells, it is all about time. Interferons work by interfering with viral replication, but to do that it must have a functioning signalling pathway. If the pathway is working, the signal goes out to upregulate and express hundreds of antiviral genes that target and disrupt the working of the virus in various ways. Therefore, the virus can be obliterated by a massive ‘first strike’ attack directed by the host interferons.
However, if the virus damages the interferons’ signalling pathway before the signal reaches the anti-viral genes, it’s a different story. There is no first strike in this scenario because the order to attack the virus never reaches the antiviral genes, or gets there in garbled form. This is precisely what HCV and RSV can do, according to findings by Dr Stevenson and his team. It means that the virus is not stopped in its tracks, but can continue to replicate and infect and depress the natural immune system. The research that found HCV targets the interferon pathway was done in collaboration with St Vincent’s University Hospital, Dublin, and funded by the Health Research Board (HRB), said Dr Stevenson.
The focus of Dr Stevenson’s research has been about trying to understand basic scientific questions, such as how do viruses target the immune system. However, he has also reached out to collaborate with clinicians so that the effects can be investigated in patients. The ambition is to translate basic molecular discoveries into a new therapeutic and this requires access to patient samples, he said.
Dr Stevenson collaborates with hepatologists at St Vincent’s University Hospital and St James’s Hospital, Dublin. He is co-supervising two PhD students that are medical consultants and training to become academic clinicians. There is also collaboration with the Children’s University Hospital, Temple Street, Dublin, involving an investigation of HCV infection in children. The medical link with patients is crucial and it means samples can be analysed at Trinity, he said.
There have been significant changes in the treatment of HCV since Dr Stevenson began his research on the virus in 2008. The only treatment available at that time was interferon and ribavirin. This combination therapy didn’t work in about half of HCV patients. His team worked out that the HCV signalling pathway was being destroyed by the virus. New therapies were designed to target the virus directly: direct-acting antivirals (DAAs). The first DAAs appeared in 2012, but interferon was still required as part of the therapy. However, the newest DAAs, which came out in 2016, do not require the use of interferon.
While the replication of HIV can be stopped, it is very hard to get rid of all the cells that contain HIV
The newest DAA is called sofobuvir, made by Gilead. It is so effective that it has revolutionised treatment therapy for HCV, said Dr Stevenson. He would like to test a hypothesis that this new drug can reduce the level of HCV enough to allow the natural interferon response to kick back in. The major problem with the use of sofobuvir is the cost. One tablet costs €563.82, while a full 24 course of treatment is €94,722, according to the National Centre for Pharmacoeconomics (NCPE), the body tasked with assessing the cost-effectiveness of medicines.
Dr Stevenson is involved in the Irish Hepatitis C Outcomes Research Network (ICORN), the leading platform for HCV clinical research in Ireland. He notes the work of ICORN in terms of advocating for medication access.
Infection with HCV is a global problem affecting 3 per cent of people worldwide, or 180 million individuals. Many of these people are living in developing countries and will generally not have access to sofobuvir. In Ireland, the US and UK, about 1.5 per cent of the population have HCV, but the percentage is much higher in some other countries such as Egypt (about 15 per cent).
The issue of cost is an ethical one. While drug companies are coming up with big drugs that really work, they will only be readily available to people living in countries where their government can afford to pay, said Dr Stevenson. Drugs cost money to be developed and it can take years of basic research to identify potential drugs. Moreover, pharmaceutical companies make significant investments to put promising targets through clinical trials, and most targets don’t come to anything. The companies must make money at the end of the day, although it is open to question how much money they need to make, he added.
Every viral genotype is different and this genetic difference can be crucial. For example, HCV genotype 1, which is the most common seen in Ireland, is involved in degrading the interferons’ signalling pathway. The same genetic sequences that enable genotype 1 to do that are not present in genotype 3. Dr Stevenson said this explains why 80 per cent of people [genotype 3] that underwent interferon and ribavirin treatment in the past responded to it, while the number of genotype 1 responders to the same treatment was far lower.
Many questions remain about why some people have better immune systems when it comes to HCV and other viruses. But the field of research into HCV is becoming less attractive to researchers, because there are so many brilliant drugs for HCV coming online, explained Dr Stevenson.
There is still a huge amount of work to be done in respect of HCV and other viruses such as HIV, where therapies can suppress the virus but not clear it from the system and provide a cure. He said there were huge advances against HIV made in 1995, with the development of antiretroviral therapies.
The key problem with HIV is that, unlike HCV, it can cut into the immune cell’s DNA and paste its own DNA in, said Dr Stevenson. Once it has done so, it is very hard to identify and remove. There is always a latent amount of HIV in people on antiretrovirals, so when people come off this treatment the virus kicks back in and can start replicating again.
While the replication of HIV can be stopped, it is very hard to get rid of all the cells that contain HIV. This situation has led some scientists to work on treatments that involve kick-starting the HIV infection again, and then treating it once it is out in the open.
Dr Stevenson said this approach is risky. He asked whether anyone would want to have HIV kick-started in their body again. However, he believes that a more fruitful and safer approach to HIV treatment may involve enhancing the individual’s innate immune response and this is another area that he is exploring.