PMID- 19643012
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20110714
LR  - 20211028
IS  - 1476-9255 (Electronic)
IS  - 1476-9255 (Linking)
VI  - 6
DP  - 2009 Jul 30
TI  - CCR5 signalling, but not DARC or D6 regulatory, chemokine receptors are targeted 
      by herpesvirus U83A chemokine which delays receptor internalisation via diversion 
      to a caveolin-linked pathway.
PG  - 22
LID - 10.1186/1476-9255-6-22 [doi]
AB  - BACKGROUND: Herpesviruses have evolved chemokines and chemokine receptors, which 
      modulate the recruitment of human leukocytes during the inflammatory response to 
      infection. Early post-infection, human herpesvirus 6A (HHV-6A) infected cells 
      express the chemokine receptor U51A and chemokine U83A which have complementary 
      effects in subverting the CC-chemokine family thereby controlling anti-viral 
      leukocyte recruitment. Here we show that, to potentiate this activity, the viral 
      chemokine can also avoid clearance by scavenger chemokine receptors, DARC and D6, 
      which normally regulate an inflammatory response. Conversely, U83A delays 
      internalisation of its signalling target receptor CCR5 with diversion to caveolin 
      rich membrane domains. This mechanism can redirect displaced human chemokines to 
      DARC and D6 for clearance of the anti-viral inflammatory response, leaving the 
      viral chemokine unchecked. METHODS: Cell models for competitive binding assays 
      were established using radiolabeled human chemokines and cold U83A on CCR5, DARC 
      or D6 expressing cells. Flow cytometry was used to assess specific chemotaxis of 
      CCR5 bearing cells to U83A, and internalisation of CCR5 specific chemokine CCL4 
      after stimulation with U83A. Internalisation analyses were supported by confocal 
      microscopy of internalisation and co-localisation of CCR5 with caveosome marker 
      caveolin-1, after virus or human chemokine stimulation. RESULTS: U83A displaced 
      efficiently human chemokines from CCR5, with a high affinity of 0.01nM, but not 
      from DARC or D6. Signalling via CCR5 resulted in specific chemoattraction of 
      primary human leukocytes bearing CCR5. However, U83A effective binding and 
      signalling to CCR5 resulted in delayed internalisation and recycling up to 2 
      hours in the absence of continual re-stimulation. This resulted in diversion to a 
      delayed caveolin-linked pathway rather than the rapid clathrin mediated 
      endocytosis previously shown with human chemokines CCL3 or CCL4. CONCLUSION: U83A 
      diverts human chemokines from signalling, but not regulatory or scavenger, 
      receptors facilitating their clearance, while occupying signalling receptors at 
      the cell surface. This can enhance virus specific inflammation, facilitating 
      dissemination to replication sensitive leukocytes while evading clearance; this 
      has implications for linked neuro-inflammatory pathologies.
FAU - Catusse, Julie
AU  - Catusse J
AD  - Pathogen Molecular Biology Unit, Department of Infectious & Tropical Diseases, 
      London School of Hygiene & Tropical Medicine, University of London, Keppel St, 
      London WC1E 7HT, UK. ursula.gompels@lshtm.ac.uk.
FAU - Clark, David J
AU  - Clark DJ
FAU - Gompels, Ursula A
AU  - Gompels UA
LA  - eng
GR  - BBS/B/02231/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
DEP - 20090730
PL  - England
TA  - J Inflamm (Lond)
JT  - Journal of inflammation (London, England)
JID - 101232234
PMC - PMC2744670
EDAT- 2009/08/01 09:00
MHDA- 2009/08/01 09:01
PMCR- 2009/07/30
CRDT- 2009/08/01 09:00
PHST- 2009/03/24 00:00 [received]
PHST- 2009/07/30 00:00 [accepted]
PHST- 2009/08/01 09:00 [entrez]
PHST- 2009/08/01 09:00 [pubmed]
PHST- 2009/08/01 09:01 [medline]
PHST- 2009/07/30 00:00 [pmc-release]
AID - 1476-9255-6-22 [pii]
AID - 10.1186/1476-9255-6-22 [doi]
PST - epublish
SO  - J Inflamm (Lond). 2009 Jul 30;6:22. doi: 10.1186/1476-9255-6-22.