Editorial: “Stealthy virus presents unique public health challenge“
MOST of us could gain extra years of life by ridding ourselves of a virus we don’t even realise we are carrying – if new efforts to tackle the stealthy parasite bear fruit.
Between 50 and 80 per cent of people living in the UK, US and Australia are infected by cytomegalovirus, or CMV – a herpes virus closely related to the one that causes chickenpox. In some African countries, the figure is thought to be even higher.
Advertisement
CMV can lead to brain damage and hearing loss in newborns, but was long assumed to be harmless in healthy adults, says , an epidemiologist at the University of Michigan in Ann Arbor. “Then HIV came along.”
When people are infected with CMV and HIV, they can develop all sorts of nasty complications, such as CMV retinitis, which causes blindness. As researchers investigated further, they realised that the damaging effects of CMV were caused by its unique effect on the immune system.
Your body responds to any infection by training a small number of immune cells to recognise and remember the pathogen in future. CMV somehow cheats the system. When the virus next attacks you, the immune T-cells trained to remember the virus do not work as they should. Instead, the body trains up a fresh batch of T-cells to recognise CMV, eating into your limited supply of untrained cells. Over time, around 40 per cent of T-cells may be trained specifically to attack CMV, leaving fewer to tackle other possible infections.
“When the virus attacks, the immune cells formerly trained to remember it do not work as they should”
A slew of research shows that this continual using up of untrained T-cells ages the immune system. The latest study suggests that this takes its toll on life expectancy.
For 18 years, at the University of Birmingham, UK, and his colleagues followed the health of more than 500 people over the age of 65. Around 70 per cent of the people were infected with CMV. “We saw a four-year reduction in lifespan in the CMV-positive group,” says Moss, who presented the findings at the in Boston, last month.
To put that figure in perspective, Aiello says: “Smoking and drinking can take that much time off your life.”
Those infected with CMV were more likely to die from cardiovascular disease, says Moss. The virus has also been linked to and – and it may leave the body more susceptible to other infections, such as flu.
Now the good news: Moss’s team reckons that long-term treatment with antiviral drugs could help claw back those years.
His team infected 6-week-old mice with CMV and, once the rodents were 6 months old and the virus was established, they treated some of them with a drug used to treat herpes viruses. While the number of untrained immune cells dwindled in the untreated mice, numbers remained high in the mice given antivirals. “We were able to completely reverse this particular effect of CMV,” says Moss. What’s more, the treated mice appeared more resilient to being infected with flu further down the line, and lost less weight during that infection than their untreated counterparts. Moss presented this study in Boston, too.
He will soon begin trialling the antivirals in people over 65. “If we can strengthen the immune systems of older people, we will hopefully see a reduction in the incidence of flu infection, as well as reduced morbidity and mortality,” he says.
Any treatment, however, might require people to take the drugs for months, if not years. What would be better, says at the University of Cambridge, would be to prevent infection in the first place by developing a vaccine.
“For CMV, the thing you want to stop is the primary infection,” he says. Finding a way to block the entry of the virus will be tricky, though, partly because no one is sure exactly how CMV infects people.
The same problem applies to Epstein-Barr virus (EBV) – a related virus that can cause glandular fever and cancer. A 30-year-long research programme to generate a vaccine for it failed, says Stevenson, because it began with an assumption that EBV first infects the body through the immune system’s B-cells. This was where the virus was spotted in people presenting with symptoms.
To investigate whether the virus may be infecting other cells first, Stevenson’s team turned to a mouse model. They were able to make the virus glow by adding a gene for a light-emitting protein found in fireflies. When Stevenson studied the mice a day after they had been infected, he found that the cells in their noses were the ones glowing ().
“The day after the mice had been infected, the cells in their noses were the ones glowing”
Since then, Stevenson’s team have been trying to figure out exactly which cells in the nose are infected first. Viruses like EBV and CMV are known to bind to cells by attaching to a sugar called heparan sulphate, found on the surface of some cells. The only cells in the nose that have the sugar in the right place to bind viruses are those involved in smell. When the group modified EBV so that it could no longer bind to heparan sulphate, they found that the chance of infection dropped to just one-hundredth of that seen with the regular virus.
Using antibodies that stop the virus from binding to the sugar could be an option for a vaccine to stop infection, says Stevenson, who presented the findings at a in London this week.
It remains to be seen whether CMV infects us in the same way as EBV, but if it does and the olfactory cells in the nose are involved, it could provide new targets for a vaccine that protects people from getting infected in the first place.
“We want to try to improve immune function and increase lifespan,” says Moss. “That’s the dream.”
Hijack a virus to treat cancer
Cytomegalovirus is one of a kind. Its ability to infect us for life and trigger new immune responses every time it reactivates means it is accelerating the ageing of many people’s immune systems (see main story). The unique talents of CMV – pictured, right – are now being exploited by researchers working on a cancer vaccine.
Tumour cells have proteins on their surface which the immune system recognises. The problem is that because these cancerous cells are our own, the immune system ignores them. “Your immune system has been educated not to attack itself,” says at the University of Connecticut at Farmington. As a result, the tumour goes unchallenged.
Khanna and his student Zhijuan Qiu have been working on a way to get the immune system to attack tumours. They modified a protein expressed by over 90 per cent of melanoma tumours just enough to encourage the body to treat it as foreign while simultaneously recognising it for the protein that it is. Then they inserted the genetic code for this protein into CMV.
The immune systems of mice infected with this modified form of CMV trained up immune T-cells to attack the virus – the idea being that these T-cells will also attack tumour cells that are expressing the protein.
The team then gave the mice a particularly bad skin cancer. While the untreated group of mice died within 23 days, the treated mice survived for as long as they were monitored – more than two months. “This is huge for mice,” says Qiu, who presented the findings at the American in Boston last month.
CMV triggers a new immune response every time the virus reactivates, so the mice’s immunity to cancer doesn’t weaken over time, as it would with other vaccines.
The researchers hope to develop their vaccine for people with a family history of cancer.
