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RANTES binding and down-regulation by a novel human herpesvirus-6 beta chemokine receptor
R S Milne1, C Mattick, L Nicholson
1Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine and Kings's College School of Medicine and Dentistry, University of London, United Kingdom.
Abstract:
The human herpesvirus 6 (HHV-6) U51 gene defines a new family of betaherpesvirus-specific genes encoding multiple transmembrane glycoproteins with similarity to G protein-coupled receptors, in particular, human chemokine receptors. These are distinct from the HHV-6 U12 and HCMV US28 family. In vitro transcription and translation as well as transient cellular expression of U51 showed properties of a multiple transmembrane protein with a 30-kDa monomer as well as high m.w. aggregates or oligomers. Transient cellularly expressed U51 also appeared to form dimeric intermediates. Despite having only limited sequence similarity to chemokine receptors, U51 stably expressed in cell lines showed specific binding of the CC chemokine RANTES and competitive binding with other beta chemokines, such as eotaxin; monocyte chemoattractant protein 1, 3, and 4; as well as the HHV-8 chemokine vMIPII. In epithelial cells already secreting RANTES, U51 expression resulted in specific transcriptional down-regulation. This correlated with reduced secretion of RANTES protein into the culture supernatants. Regulation of RANTES levels may alter selective recruitment of circulating inflammatory cells that the virus can infect and thus could mediate the systemic spread of the virus from initial sites of infection in epithelia. Alternatively, chemokine regulation could modulate a protective inflammatory response to aid the spread of virus by immune evasion. Such mimicry, by viral proteins, of host receptors leading to down-regulation of chemokine expression is a novel immunomodulatory mechanism.
Insights
The human herpesvirus 6 U51 gene encodes a novel transmembrane protein that binds chemokines, down-regulating their expression. This mechanism may aid virus spread by altering inflammatory cell recruitment or immune evasion.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Human herpesvirus 6 (HHV-6) U51 gene encodes a new family of betaherpesvirus-specific transmembrane glycoproteins.
- These proteins show similarity to G protein-coupled receptors, specifically human chemokine receptors, but are distinct from other known HHV-6 and HCMV families.
Purpose of the Study:
- To characterize the HHV-6 U51 gene product.
- To investigate its interaction with chemokines and its role in viral immunomodulation.
Main Methods:
- In vitro transcription and translation.
- Transient and stable cellular expression of U51.
- Chemokine binding assays using CC chemokines like RANTES, eotaxin, MCPs, and vMIPII.
- Analysis of RANTES transcriptional and protein secretion levels in epithelial cells.
Main Results:
- U51 functions as a multiple transmembrane protein, existing as monomers, aggregates, and dimeric intermediates.
- Despite limited sequence similarity, U51 specifically binds RANTES and competitively binds other beta chemokines.
- U51 expression in epithelial cells down-regulates RANTES transcription and reduces RANTES protein secretion.
Conclusions:
- HHV-6 U51 represents a novel viral protein mimicking host chemokine receptors.
- Down-regulation of chemokines by U51 may facilitate viral systemic spread through altered inflammatory cell recruitment or immune evasion.
- This represents a novel mechanism of viral immunomodulation via chemokine receptor mimicry.