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A Gammaherpesvirus G Protein-Coupled Receptor Homologue Is Required for Increased Viral Replication in Response to Chemokines and Efficient Reactivation from Latency^{1 ,2}

Bong Joo Lee^*, Ulrich H. Koszinowski, Sally R. Sarawar^3,4,* and Heiko Adler^,

^* Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; Max von Pettenkofer-Institut fur Hygiene und Medizinische Mikrobiologie, Lehrstuhl Virologie, Genzentrum, Ludwig-Maximilians-Universitat Munchen, Munich, Germany; and GSF Research Center for Environment and Health, Institute of Molecular Immunology, Clinical Cooperation Group, Hemopoietic Stem Cell Transplantation, Munich, Germany

The open reading frame (ORF) 74 of gamma-2-herpesviruses encodes a G protein-coupled receptor which is highly conserved in members of this subfamily and is homologous to the CXCR2 chemokine receptor. The viral G protein-coupled receptor has been implicated in viral pathogenesis. However, the advantage of such chemokine receptor homologues to the virus is currently unknown. To address this, we constructed ORF74 deletion mutants of a mouse gamma-2-herpesvirus (MHV-68) and examined the effect of the deletion on viral growth and reactivation from latency. Growth of the mutant viruses in NIH 3T3 cells was similar to that of wild-type virus. However, CXC chemokines with ELR motifs, KC, and macrophage-inflammatory protein 2, significantly increased viral replication of the wild-type, but not the mutant viruses, via a pertussis toxin-insensitive, mitogen-activated protein/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase-dependent pathway. IFN--inducible protein 10, a CXC chemokine lacking an ELR motif, was able to reverse the effect of KC on viral replication. The mutant viruses also showed significantly reduced reactivation from latently infected mouse splenocytes. Reinsertion of ORF74 into the mutant virus restored the wild-type phenotype. Utilizing a viral CXCR2 homologue to enhance replication and reactivation from latency represents a novel mechanism by which gammaherpesviruses can subvert the immune response.

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