Eliminating CMV from the body

Scientists in Cambridge have uncovered a powerful new way to attack cytomegalovirus - CMV - which causes major infection problems and blindness for transplant patients and individuals with immune systems weakened by AIDS.

Writing inScience, Mike Weekes and his colleagues at Cambridge University have uncovered a previously-overlooked process that the virus uses to escape the immune system. Targeting it could enable scientists to rid the body of the infection.

Some people will be surprised to learn that over half of the population are carriers of CMV, which causes a transient flu-like illness when it first infects before it lurks, in a dormant state, inside immune cells called monocytes.

From this so-called latent condition, the virus can periodically reactivate, causing serious damage to a range of tissues including the lungs, intestines and eyes.

This usually happens when the immune system is weakened by diseases, like HIV, or immune-suppressing anti-rejection drugs given to transplant patients and people with inflammatory conditions.

Presently, doctors can control some of the acute symptoms of the infection, although it is impossible to rid the body of the dormant form of the virus meaning that it frequently recurs causing ill-health and progressive organ damage.

But using a process called plasma membrane profiling, the Cambridge team were able to spot that a chemical marker called MRP1, which is normally present on the surfaces of cells, disappears when the cells are harbouring latent CMV.

A gene in the virus, called UL138, is responsible, and causes MRP1 to be broken down inside infected cells. Cells that lack MRP1 fail to respond to signals instructing them to visit lymph glands where the immune system would otherwise be able to mount a response against the virus.

This, the team speculate, is the underlying immune-evasion strategy on the part of the virus. But, therein lies the solution, because the absence of MRP1 can actually be used as a sensitive marker to single out and potentially remove infected cells.

Furthermore, MRP1 normally acts as a transporter, pumping out substances including some toxic drugs from inside cells.

This means that, because CMV-infected cells lack MRP1, they are actually more vulnerable to certain drugs including one called vincristine, which builds up inside and destroys them.

To find out whether this might work therapeutically, the team took blood samples from 15 CMV-infected patients, exposed the cells in a dish to low levels of vincristine, and then attempted to reactivate any latent CMV in the sample.

The result was no, or almost no, CMV reactivation, suggesting that CMV-infected cells become selectively vulnerable to vincristine therapy, suggesting that the same might workin vivo...