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Study offers insights into common human infection

Understanding of a widespread herpes virus is aided by genetic discoveries about its interaction with immune proteins.

Microscope image of ZAP expression
Proteins arising from the ZAP gene inhibit the replication of HCMV in cells.

Discoveries of how the human immune system fights a common virus – and how the virus avoids detection – have been made in a study led by researchers at the Roslin Institute.

Scientists have pinpointed a protein with a key role in preventing infection with human cytomegalovirus (HCMV)  ̶  a widespread virus that is often harmless but which can cause serious illness in transplant patients as well as congenital conditions.

The virus can circumvent detection by the anti-viral protein owing to its genetic makeup, allowing it to establish infection in the body, the research team found.

Their insights could inform further studies towards developing vaccines to prevent viral infection.

Gene shortlist

Researchers sought to better understand how the immune system recognises and defends the body against HCMV, by screening more than 400 genes that might be important in responding to the virus.

Their results identified a handful of possible genes including two, known as ZAP and TRIM25, which previous studies had suggested might collectively have a part to play.

Further investigation showed that proteins arising from both of these genes inhibit the replication of HCMV in cells - high levels of ZAPS and TRIM25 protein reduced replication of the virus, while their absence led to increased virus.

Avoiding detection

To investigate how HCMV establishes infection in the body, the team looked into its genetic makeup.

Viral genes that are involved in the early stages of infection differ in their biological composition – composed of components labelled C, G A and T – from other genes in the virus.

These early genes have few instances where C is followed by G, similar to the pattern in human genes.

This similarity enables the virus to avoid detection by antiviral genes such as ZAP, the team found.

The virus, once established, is then able to block the body’s immune response to cause infection.

Viral genes expressed at later stages of infection have a higher proportion of CG pairs, which may be because they no longer need to avoid detection by the immune system.

Insights from the study could inform development of antiviral vaccines based on exploiting the CG patterns in the virus.

The study, published in PLoS Pathogens, was carried out in collaboration with the Universities of Glasgow and Oxford and Oregon Health and Science University in the US.

We have identified a gene that inhibits replication of the human cytomegalovirus, but the virus is able to avoid detection by this gene in the early stages of infection owing to its genetic makeup, and establish itself in the body to create infection. More work to understand these fundamental findings in detail could inform development of sophisticated vaccines against viral infection such as HCMV.

Dr Finn GreyRoslin Institute

** The Roslin Institute receives strategic investment funding from the Biotechnology and Biological Sciences Research Council and it is part of the University of Edinburgh’s Royal (Dick) School of Veterinary Studies. **

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