NDLI: Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Clark, D. J. Catusse, J. Stacey, A. Borrow, P. Gompels, U. A.
Description	Country affiliation: United kingdom Author Affiliation: Clark DJ ( Pathogen Molecular Biology Department, London School of Hygiene and Tropical Medicine, University of London, Keppel St., London WC1E 7HT, UK.)
Abstract	Human monocytes expressing CCR2 with CD14 and CD16 can mediate antigen presentation, and promote inflammation, brain infiltration and immunosenescence. Recently identified roles are in human immunodeficiency virus infection, tuberculosis and parasitic disease. Human herpesvirus 6B (HHV-6B) encodes a chemokine, U83B, which is monospecific for CCR2, and is distinct from the related HHV-6A U83A, which activates CCR1, CCR4, CCR5, CCR6 and CCR8 on immune effector cells and dendritic cells. These differences could alter leukocyte-subset recruitment for latent/lytic replication and associated neuroinflammatory pathology. Therefore, cellular interactions between U83A and U83B could help dictate potential tropism differences between these viruses. U83A specificity is maintained in the 38-residue N-terminal spliced-truncated form. Here, we sought to determine the basis for the chemokine receptor specificity differences and identify possible applications. To do this we first analysed variation in a natural host population in sub-Saharan Africa where both viruses are equally prevalent and compared these to global strains. Analyses of U83 N-terminal variation in 112 HHV-6A and HHV-6B infections identified 6/38 U83A or U83B-specific residues. We also identified a unique single U83A-specific substitution in one U83B sequence, 'U83BA'. Next, the variation effects were tested by deriving N-terminal (NT) 17-mer peptides and assaying activation of ex vivo human leukocytes, the natural host and cellular target. Chemotaxis of CCR2+ leukocytes was potently induced by U83B-NT, but not U83BA-NT or U83A-NT. Analyses of the U83B-NT activated population identified migrated CCR2+, but not CCR5+, leukocytes. The U83BA-NT asparagine-lysine14 substitution disrupted activity, thus defining CCR2 specificity and acting as a main determinant for HHV-6A/B differences in cellular interactions. A flow-cytometry-based shape-change assay was designed, and used to provide further evidence that U83B-NT could activate CCR2+CD14+CD16+ monocytes. This defines a potential antiviral target for HHV-6A/B disease and novel peptide immunomodulator for proinflammatory monocytes.
File Format	HTM / HTML
ISSN	00221317
Issue Number	Pt 7
Volume Number	94
e-ISSN	14652099
Journal	Journal of General Virology
Language	English
Publisher	Microbiology Society
Publisher Date	2013-07-01
Publisher Place	Great Britain (UK)
Access Restriction	Subscribed
Subject Keyword	Chemotaxis, Leukocyte Research Support, Non-u.s. Gov't Peptides Discipline Virology Antigens, Cd14 Humans Viral Proteins Inflammation Metabolism Drug Effects Herpesvirus 6, Human Journal Article Receptors, Igg Monocytes Immunology Flow Cytometry Genetics Receptors, Chemokine Receptors, Ccr2 Chemokines Methods
Content Type	Text
Resource Type	Article
Subject	Virology

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