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
© Catusse et al; licensee BioMed Central Ltd. 2009
Received: 24 March 2009
Accepted: 30 July 2009
Published: 30 July 2009
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.
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.
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.
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.
Human herpesvirus 6 (HHV-6) is a wide-spread blood-borne virus, causing common childhood infections, resulting in febrile disease with occasional rash (Exanthem Subitum) and further serious complications, including encephalitis . There are two variants, HHV-6A and B; HHV-6A has been linked with further neuro-inflammatory disease including multiple sclerosis (MS) and encephalopathy. HHV-6 is predominantly lymphotropic and has evolved mechanisms for the dysregulation of human immunity including diversion of chemokine activities. Chemokines interact with defined receptors expressed on specific leukocyte subsets, resulting in their activation and migration (chemotaxis) toward a chemokine gradient created by secretion from infected or damaged cells. Hence, chemokines are involved in hematopoietic cell traffic, inflammation and virus immunity as they can attract antigen presenting cells to sites of infection, mediate lymph node homing or activate immune defence mechanisms. To overcome the chemokine defence mechanism and redirect it towards enhanced virus persistence, HHV-6 encodes two chemokine receptors (U12 and U51) and one chemokine (U83) [2–5]. These are potential virulence factors in linked inflammatory pathologies. Furthermore, U83 is the only HHV6-specific hypervariable gene, and therefore key for biological differences between HHV-6 A and B strains. Laboratory adapted strains can have mutations affecting U83 expression, but both wild-type variants can encode signal sequences mediating chemokine secretion . U83A from HHV-6A is a high affinity broad-range yet selective agonist for CC-chemokine receptors CCR1, CCR4, CCR5, CCR6 and CCR8, while HHV-6B U83B is a low affinity CCR2 ligand [2, 4]. This disparity suggests U83 plays a key role in tropism and pathology differences between variant strains. Moreover, recent reports demonstrate HHV-6 integrations in the germ line of approximately 1% of the population [6, 7], thereby giving expression of U83 the potential to exhibit as a human chemokine allele, not only from widespread latent infection, but also as part of the human genomic complement. Thus, it is important to establish effects of U83A in an inflammatory response.
Human chemokines and their receptors targeted by early HHV-6A infection
Affected* signalling Receptors
Affected scavenger receptors
CCR1, 3, 5
CCR1, 2, 3
CCR1, 2, 3
CCL3, 4, 5
There are three 'atypical' or scavenger chemokine receptors with roles in regulation of the chemokine system namely D6, DARC (Duffy antigen/receptor for chemokines) and CCX-CKR (chemocentryx chemokine receptor). Both D6 and DARC clear chemokines that bind signalling receptors CCR1, CCR2, CCR3, CCR4 and CCR5. In addition, DARC targets chemokines for receptors CXCR1 and CXCR2. CCX-CKR seems to have a more narrow spectrum, comprising chemokines which bind receptors CCR7, CCR9 and CXCR5 [12, 15] (Table 1). Signalling receptors respond to human chemokines as well as viral chemokine U83A binding by inducing G-protein activation, increasing intracellular calcium levels, and various signalling cascades leading to cell polarisation, cytoskeletal changes, and chemotaxis. We have shown previously that U83A is able to block signalling receptor function by stopping their endocytosis via clathrin coated pits . This effect was specific, since rapid clathrin-linked endocytosis of transferrin continued in the presence of U83A, and also CCL4 induced CCR5 in the absence of U83A. Here we show that U83 interferes with chemokine receptors activities via induction of their co-localisation rather with caveolin-1, in a delayed endocytic pathway. In contrast to signalling receptors, scavenger receptors bind chemokine efficiently, but do not induce known intracellular signalling pathways. Instead there is chemokine sequestration, internalisation, degradation, or re-localisation through transcytosis [12, 15–17]. D6 and DARC bind chemokines with specificities similar to U83A, thus they are investigated here and compared to modulatory effects on CCR5 signalling.
COS-7 cells transfected with indicated receptors as described  (1 × 106), were incubated in Binding buffer (RPMI 1640, 0.1% BSA, and 20 mM HEPES, pH 7.4) for 2 h at 4°C with 125 pM of 125I radiolabelled chemokine (Perkin Elmer, specific activity: 2200 Ci/mM) in absence or presence of increasing concentrations of cold competitor viral (U83A or U83A-N)  or human chemokines (R&D Systems Europe Ltd., Abingdon, UK). After 2 h incubation on ice, cells were separated from unbound chemokine by microcentrifugation though a phthalate oil cushion (1.5 parts dibutylphthalate to 1 part bis(2-ethylhexyl)phthalate) as described [2, 4], with bound radioactivity counted with a gamma counter. Data and statistical analyses used Prism 0.1.53 software (GraphPad).
CCR5 expressing cells, MAGI-CCR5E , were incubated for 10 minutes at 37°C in absence or presence of 100 nM of U83A, washed in Binding buffer and incubated at 37°C and 5% CO2 for 30, 60 and 120 minutes before stimulation by 100 nM of CCL4 for 10 minutes or buffer only for unstimulated negative control. Cells were washed then resuspended in FACS buffer PBS, 0.1% BSA) and Fc blocked using 1 μg of human IgG/105 cells for 15 minutes at room temperature. Cells were then incubated at 4°C with fluorescein isothiocyanate, FITC, linked-CCR5 antibody (FAB 182F; R&D systems) for 30 minutes, washed three times with ice cold FACS buffer, fixed with 4% PFA and CCR5 surface expression determined as described  using a FACS calibur flow cytometer (BD Biosciences, Oxford, UK) and results analysed with FlowJo (Tree Star Inc.). Matching isotypes (mouse IgG2B) were used as negative controls and results are expressed as percentage of expression at time 0 for each treatment and subsequent incubation time.
Chemotaxis was assayed using 96 well microchemotaxis chambers (ChemoTx, Neuroprobe, Gaithersberg, MD, USA) as described  with human donor peripheral blood mononuclear cells (PBMC) supplied from healthy laboratory volunteers, with local ethical committee approval, using anonymous coded samples (one donor per experiment). PBMC were purified as described  using EDTA anti-coagulated blood centrifuged over a Histopaque 1077 cushion (Sigma Aldrich, Irvine, UK) with cells collected from the interphase, then washed twice with phosphate buffered saline. Cells were resuspended in 10 ml RPMI, 10% fetal calf serum and used either immediately or after culture in ultra-low attachment tissue culture plasticware (Corning, NY, USA) for 3 days as described . Chemokines were diluted in migration buffer, HBSS (Invitrogen, Paisley, UK) with 0.1% BSA (Sigma Aldrich, Irvine, UK) and added to the bottom chambers, including wells with buffer only negative control. A 5 μm filter was placed on top and cells resuspended in the same buffer were layered on the top filter membrane, then cultured for 1.5 hours at 37°C, 5% CO2. Cells were then gently wiped from the top membrane and the plate centrifuged for 2 minutes. Migrated cells in the bottom chambers were pooled from 8 wells per treatment and assayed for CCR2 and CCR5 expression by flow cytometry as above, with FITC-CCR5 antibody and phycoerythrin, PE, linked CCR2 antibody (FAB 151P) with isotype controls (FITC-mouse IgG2B IC004F and PE-mouse IgG2B IC004P) (R&D Systems). Chemotaxis assays were in triplicate from three independent assays of different donor cells.
As described previously , U373-MAGI-CCR5E cells were grown on coverslips for 24 hours then starved in serum-free medium for 30 minutes at 37°C, 5%CO2. After one washing in pre-warmed serum-free medium at 37°C, the cells were incubated with chemokines for 10 or 30 minutes. Cells were then permeabilized, by treatment with 0.05% saponin in 0.5% BSA-PBS for 10 minutes and then labelled with a buffer containing tetramethylrhodamine B thioisocyanate, TRITC-anti-human caveolin polyclonal antibody (Sc894, Santa Cruz Biotechnology Inc., CA, USA) and FITC-anti-human CCR5 monoclonal antibody (R&D Systems, UK) as described . Next, the labelled cells were washed three times in ice-cold PBS containing 0.5% BSA, followed by fixation in 3% paraformaldehyde for 10 minutes. After three washings in ice-cold PBS containing 0.5% BSA, free aldehyde groups were quenched with 50 mM NH4Cl in PBS for 10 minutes. The coverslips were washed three times in PBS and then mounted using Vectashield mounting solution containing DAPI for nucleus detection (Vector Laboratories, Burlingame, CA, USA). Cells were examined using Z-stack sections (at 0.39-μm interval), and pictures acquired on a Zeiss LSM 510 Axioplan microscope with a Plan-Apochromat 63×/1.4 oil objective by an AxioCam with magnification ×630 under oil immersion (Zeiss, Jena, Germany). Digital images were analyzed with Zeiss LSM Image Browser, version 188.8.131.526 [EC] (AxioCam). Fluorochromes were excited at 488 nm for FITC and 542 nm for TRITC.
U83A efficiently displaces human chemokines from CCR5 signalling chemokine receptor in model system to compare to regulatory receptors
U83A does not displace human chemokines from DARC and D6 regulatory receptors
U83A induces specific chemotaxis of human leukocytes bearing CCR5
U83A delays CCR5 internalisation and blocks stimulation by human chemokine
Percentage of CCR5 surface expression after U83A or U83A-N treatment followed by CCL4 stimulation
Time CCL4 stimulation
Diversion by U83A of CCR5 internalisation via delayed caveolin linked pathway
Results show that U83A exercises a complex and thorough control of CCR5 signalling receptor activity, while bypassing clearance by D6 or DARC regulatory receptors (Table 1). This could account for unregulated U83A activity in chronic inflammatory disease linked with HHV6-A, including neuroinflammatory pathology such as MS and encephalitis [24, 25].
D6 is involved in a rapid and constant constitutive internalisation and degradation of circulating human chemokines. Binding of chemokine to D6 does not result in the activation of major chemokine signalling pathways and thus restrains the inflammatory process by competition. A role of D6 in MS has been indicated through its involvement in chemokine clearance to regulate inflammation as well as alteration of immune cell localisation hence impairment of immune function . D6 expression has been demonstrated on lymphatic endothelial cells, in skin, gut and lungs with roles as a chemokine sequestering decoy . It is also implicated in clearance of chemokines in placenta; D6-/- mice show increased miscarriage indicating D6 expression protective [13, 27]. Furthermore, congenital and placental infections with HHV-6A/B have been demonstrated as well as virus reactivation during pregnancy [28, 29]. Case reports show infections in rare seronegative women with spontaneous abortion and neuro-inflammatory complications in the newborn after HHV-6 transplacental infection, and primary infected infants [30–32].
DARC can be considered a chemokine buffer, acting as a chemokine reservoir when expressed on erythrocytes . It is also expressed on vascular endothelial cells and a role in transcytosis, supporting leukocyte migration, has been proposed; it is up-regulated in several inflammatory diseases [17, 34–37]. DARC upregulation has been associated with acute renal transplant rejection , and co-localisation of DARC and CCR5 expressing cells has been suggested as a common process during graft rejection, with implications for HHV-6 association with acute renal graft rejection . Here we show U83A can avoid DARC but still attract CCR5 expressing cells. Unregulated U83 may drive other inflammatory pathologies, such as HHV-6 associated myocarditis [39, 40], since autoimmune myocarditis is escalated by CCR5-bearing activated T-cells and monocytic/macrophages , which can be chemoattracted by U83A.
Multifaceted interactions of CCR5 with caveolin rich membrane regions (or rafts) are suggested in a recent report  which shows that signalling induced by receptors expressed in these regions differs from signalling induced by receptors expressed elsewhere. Raft domains are often described as favouring the interactions between surface expressed receptors and intracellular activation pathways, (e.g CXCR1 partitioning to lipid raft is assumed to enhance its activity ). However it is likely that it only modifies the coupling rather than induces it, as for example CCR5 can signal in absence of raft . At the virus level, it is also noteworthy that U51, one of the HHV6 encoded chemokine receptors which binds and is activated by CCL5, can establish unusual coupling to G proteins. U51 can induce pertussis toxin (PTX)-insensitive increases in phospholipase C activity and changes in intracellular free calcium concentration, which are Gq modulated, while different ligands can re-direct to a Gαi linked pathway . Gathering CCR5 to a caveolin raft where Gq coupling is favoured , might also facilitate U51 coupling to Gαi elsewhere. Thus redirecting CCR5 to a raft membrane microdomain, can be another pathway to control its activity to avoid its internalisation and to direct signalling.
Finally, extended CCR5 blocking could lead to enhanced U83A displacement of HIV-1 from the co-receptor CCR5, since only the human chemokines which also compete, such as CCL5, can be cleared by DARC or D6. This would also enhance the competitive inhibition of HIV-1 infection we have previously demonstrated by U83A . To our knowledge this internalisation inhibition by a heterologous chemokine is unique. CCR5 is a key signalling molecule to infection. For HIV-1 it not only serves as co-receptor, but activation via CCR5 is important in development of an efficient immune response to the infection [45, 46]. CCR5 is expressed on plasmacytoid and immature myeloid dendritic cells, plus monocytic/macrophages, NK cells as well as key T cell subsets such as TH1, naive CD8, and some Treg cells, thus important in protective inflammatory responses in infected tissue sites [15, 47]. It is essential for developing a TH1 cell response, which controls intracellular virus infections. Although deletion of CCR5 surface expression as observed in the CCR5delta32 mutation provides protection against HIV-1 infection, blocking as well as stimulation of CCR5 via efficient human chemokine CCL3L1 can also enhance protection, similar to the activities shown here by viral U83A chemokine . Further, CCR5 expression promotes resistance to West Nile Virus infections . In HHV-6A, CCR5 effects are targeted on multiple levels. U83A displaces human chemokines from binding, and also delays internalisation and hence recycling of unbound CCR5. It diverts CCR5 to signalling via a caveolin-linked pathway, which still allows chemotaxis, but delays signalling via human chemokines, hence only recruitment of cells susceptible for infection rather than activated cells for immunity and clearance. The displacement of human chemokines, both by competitive binding and delayed internalisation preventing restimulation, can act as a co-factor to DARC and D6, which can bind and sequester these human ligands of CCR5. This would raise the levels of chemokines recognised by D6, which can induce its membrane expression and further enhance chemokine degradation . Furthermore, HHV-6A U51 chemokine receptor can both bind and downregulate expression of CCL5, which normally interacts with CCR5. To sum up, U83A permits continued sequestering of human chemokines via regulatory receptors away from an infectious centre, while occupying the human signalling receptors, preventing their physiological recycling, directing CCR5 to a different internalisation pathway and displacing normal interactions with endogenous chemokines.
U83A effects add to the increasing evidence for pivotal roles played by receptor internalisation regulation in the complexity of cell responses to chemokines. In contrast to the full-length U83A effects, the spliced truncated U83A-N, had lower affinity binding, did not mediate specific chemotaxis, and had no significant effects on internalisation. Similarly, CCR7 is differentially internalized according to the stimulating ligand (CCL19 or CCL21), suggesting different functions or regulation of these two otherwise redundant chemokines . While differential internalisation efficiency of CCR3 by different chemokines was also demonstrated with eotaxin/CCL11 versus RANTES/CCL5 . Recent results also show further inhibition mechanisms, where dimerisation of DARC with receptor CCR5 prevents chemotaxis without affecting internalisation . This inhibitory effect would also be amplified with U83A interaction with CCR5 preventing recycling and exposure to signalling chemokines.
HHV6 U83A has developed a double ability to escape clearance by avoiding regulatory scavenger chemokine receptors and by delaying internalisation/recycling of their classical target signalling receptors, therefore together with previously defined agonist activities and complementary effects of the virus chemokine receptor, these actions provide molecular mechanisms for linked inflammatory pathologies, such as MS, as well as applications for novel immunomodulators.
We thank the BBSRC-UK for support (UAG and JC) plus LSHTM for a PhD studentship (DJC) and Drs Y. Colin and C. Tournamille, INSERM U665, Paris, France, for providing a DARC expression plasmid, Dr C.M. Parry, UK Health Protection Agency, London for U373-MAGI-CCR5E cells, as well as Dr T. Ward and C. Stanley, LSHTM, for confocal microscopy advice and phlebotomy, respectively.
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