Most people are infected with human cytomegalovirus (HCMV). If they are healthy, their immune system can keep it under control. The virus normally conceals itself inside our white blood cells, but it can flare up if the immune system becomes weakened or if it is suppressed. This can be lethal for patients undergoing cell- or organ transplants.
In a study published in Nature Communications, a team of scientists led by professors Martine Smit (VU Amsterdam) and John Sinclair (University of Cambridge) developed a new method for recognizing and clearing any virus particles that are concealed inside cells, using a specific type of antibody fragment.
Human antibodies consist of two ‘heavy’ chains of molecules and two ‘light’ ones. Together, these chains recognize antigens on the surface of a cell or virus, and bind to them. However, in the case of a special class of antibodies found in camelids (e.g. dromedaries, llamas and alpacas), a single fragment of antibody is sufficient to effectively recognize antigens. Such fragments are also referred to as ‘nanobodies’. Nanobodies have recently been approved for the treatment of blood clots in small blood vessels. Other nanobodies are already being used in clinical studies into certain forms of cancer, for example.
Reactivation of the virus
The VU Amsterdam research team has succeeded in developing nanobodies that target US28 – a protein specific to human cytomegalovirus. Timo De Groof, one of the article’s authors, explains that “The protein US28 is known to play a key part in maintaining latent HCMV infections. This led us to believe that partial inhibition of this protein could help to reveal and clear any infected cells.”
Researchers at Prof. John Sinclair’s lab were able to confirm this hypothesis. When they used nanobodies to partially inhibit US28 signalling in infected blood cells, this did indeed result in a partial reactivation of the virus. This enables immune cells to ‘see’ and clear the reservoir of latently infected cells, while avoiding the formation of new virus particles. The blood is, as it were, cleansed of infected cells.
This could form the basis of a therapeutic approach with a novel mechanism of action. It could be used as a preventive treatment for patients undergoing cell- or organ transplantation, who are at risk of serious HCMV-related diseases. Prof. Martine Smit of VU Amsterdam adds “We believe that our approach could lead to a new kind of treatment for reducing – and possibly even preventing – HCMV infections in patients who are eligible for organ- or stem cell transplantation.”