Herpes 3D: NMR reveals viral protein hijacking

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  • Published: Jan 15, 2011
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Herpes 3D: NMR reveals viral protein hijacking

Docking disease

UK scientists have used solution-state NMR spectroscopy for the first time to develop a 3D picture of a herpes virus protein interacting with a key part of the human cellular machinery. The study improves our understanding of how the virus hijacks human cells and could eventually lead to new targets for drug therapy.

Herpes simplex is a viral disease caused by both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The two most common infections are oral herpes, which causes cold sores, also known as fever blisters, and affects the face and mouth. Genital herpes, although less common is an important sexually transmitted infection (STI), herpes. Antiviral treatment is available to reduce viral shedding and alleviate the severity of symptoms, but there is no cure. Vaccines are currently going through clinical trials but efficacy remains to be demonstrated.

Now, Alexander Golovanov of the University of Manchester's Interdisciplinary Biocentre and Faculty of Life Sciences and colleagues there and at the Universities of Sheffield and Leeds, have uncovered an important clue using NMR spectroscopy regarding the herpes viral lifecycle.

Virally mild to serious

"There are quite a few types of herpes viruses that cause problems as mild as cold sores through to some quite serious illnesses, such as shingles or even cancer," explains Golovanov. "Viruses cannot survive or replicate on their own - they need the resources and apparatus within a human cell to do so. To prevent or treat diseases caused by viruses we need to know as much as possible about how they do this so that we can spot weak points or take out key tactical manoeuvres."

The researchers have derived a three-dimensional model of a key herpes protein and shown how it "piggybacks" on the host cells' molecular machinery to promote viral replication and to spread infection through the body. "When you look at the image, the small compact fragment of viral protein fits nicely on the back of the human protein," explains Golovanov.

The 3D images of this viral-human protein-protein docking coupled with biochemical experiments has revealed the mechanism by which the viral proteins - HSV-1 ICP27 and HVS ORF57 - co-opts the human cellular protein - mRNA Export Factor REF - to guide the virus's genetic material out of the cell's nucleus and into the cytoplasm. The function is triggered by binding to proteins of the transcription-export (TREX) complex, in particular to REF/Aly which directs viral mRNA to the TAP/NFX1 pathway and, subsequently, to the nuclear pore for export to the cytoplasm. Once there, the genetic material can be utilized to make proteins that are used as building blocks for new viruses. The researchers have also confirmed that this relationship between the two proteins exists for related herpes viruses that infect monkeys.

Step towards herpes treatment

"Our discovery gives us a whole step more detail on how herpes viruses use the human cell to survive and replicate," says Golovanov. "This opens up the possibility of asking new questions about how to prevent or treat the diseases these viruses cause."

"We have identified the pattern of residues critical for REF/Aly recognition, common to both ICP27 and ORF57," the team explains. They have also confirmed the importance of the key amino acid residues within these binding sites using site-directed mutagenesis. The researchers also tested the functional significance of the docking of viral to human proteins using an ex vivo cytoplasmic viral mRNA accumulation assay. "This revealed that mutants that reduce the protein-protein interaction dramatically decrease the ability of ORF57 to mediate the nuclear export of intronless viral mRNA," the team explains. Taken together the structural data and the genetic insights provide "the first molecular details of how herpes viruses access the cellular mRNA export pathway."

This could represent a new and detailed target for antiviral drug discovery. However, Golovanov cautions that it is still too early in this research to suggests that a herpes cure might be on the horizon. "In reality, the situation is a bit more complex than this," he told SpectroscopyNOW. "Although this particular interaction may not be an immediate target for antiviral drug discovery due to some functional redundancy of cellular components that viruses hijack, further similar work in this area using solution NMR techniques may identify another interface between viral and cellular proteins which will be more suitable for structure-based drug design." He adds that, "At the moment we just started to look at the tip of an iceberg, and this is the first application of high-resolution NMR to structural studies of viral mRNA export promoted by ICP27." Further work in this area is now in progress.

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

 An image of a human cellular protein (white) with a herpes virus protein docked (red) showing the details of the interaction leading to increased export of viral genetic material from the cell nucleus, so as to build a new generation of viruses. Image: Drs Alexander Golovanov and Richard Tunnicliffe, The University of Manchester.
Herpes virus protein (red) docks with human cellular protein (white)

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