The role of RL13 in human cytomegalovirus pathogenesis

Human cytomegalovirus (HCMV) infects the majority of individuals worldwide, producing a lifelong infection that dramatically alters the immune system.

If caught during pregnancy, it can lead to death of the foetus, or the foetus can be born with permanent disabilities including mental retardation, deafness or blindness.

This affects >1,000 babies every year in the UK - more than downs syndrome. However HCMV also offers a unique possibility. By far the strongest immune response raised to any infectious agent is made to CMV, and following animal studies, CMV has unexpectedly emerged as the best candidate vaccine carrier against human immunodeficiency virus (HIV).

The advent of CMV as a vaccine carrier, and the need to develop anti-HCMV vaccines, has highlighted fundamental virological issues that need to be urgently addressed. When clinical isolates are grown in the laboratory, they change. They rapidly lose the ability to infect a wide range of cell types, and become less 'cell associated'.

Consequently, it isn't possible to accurately model how well vaccines work, and how well HCMV-based vaccine carriers protect against other diseases, using lab-grown viruses. We have determined exactly how CMV changes in the lab, and developed unique technologies to reverse these changes; clinical virus contains a gene called RL13, but virus grows poorly in the lab unless RL13 is inactivated.

However once RL13 is inactivated, virus growth is dramatically altered, and virus interacts differently with the immune system. It is therefore imperative that research labs are able to work with virus containing RL13, particularly when developing vaccines and therapeutics.

This project will determine why RL13 stops virus growing in the lab. It will circumvent this limitation, enabling us to grow HCMV-based vaccine vectors containing RL13, and will determine whether RL13 is required in vaccine vectors to provide optimal protection against HIV or cancer.