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Dissecting the regions of virion-associated Kaposi's sarcoma-associated herpesvirus complement control protein required for complement regulation and cell binding

Spiller, OB ; Mark, Linda LU ; Blue, CE ; Proctor, DG ; Aitken, JA ; Blom, Anna LU orcid and Blackbourn, DJ (2006) In Journal of Virology 80(8). p.4068-4078
Abstract
Complement, which bridges innate and adaptive immune responses as well as Immoral and cell-mediated immunity, is antiviral. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a lytic cycle protein called KSHV complement control protein (KCP) that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases. These complement regulatory activities require the short consensus repeat (SCR) motifs, of which KCP has four (SCRs 1 to 4). We found that in addition to KCP being expressed on the surfaces of experimentally infected endothelial cells, it is associated with the envelope of... (More)
Complement, which bridges innate and adaptive immune responses as well as Immoral and cell-mediated immunity, is antiviral. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a lytic cycle protein called KSHV complement control protein (KCP) that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases. These complement regulatory activities require the short consensus repeat (SCR) motifs, of which KCP has four (SCRs 1 to 4). We found that in addition to KCP being expressed on the surfaces of experimentally infected endothelial cells, it is associated with the envelope of purified KSHV virions, potentially protecting them from complement-mediated immunity. Furthermore, recombinant KCP binds heparin, an analogue of the known KSHV cell attachment receptor heparan sulfate, facilitating infection. Treating virus with an anti-KCP monoclonal antibody (MAb), BSF8, inhibited KSHV infection of cells by 35%. Epitope mapping of MAb BSF8 revealed that it binds within SCR domains 1 and 2, also the region of the protein involved in heparin binding. This MAb strongly inhibited classical C3 convertase decay acceleration by KCP and cofactor activity for C4b cleavage but not CA cleavage. Our data suggest similar topological requirements for cell binding by KSHV, heparin binding, and regulation of C4b-containing C3 convertases but not for factor I-mediated cleavage of C3b. Importantly, they suggest KCP confers at least two functions on the virion: cell binding with concomitant infection and immune evasion. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Virology
volume
80
issue
8
pages
4068 - 4078
publisher
American Society for Microbiology
external identifiers
  • wos:000236685600038
  • pmid:16571823
  • scopus:33645794556
ISSN
1098-5514
DOI
10.1128/JVI.80.8.4068-4078.2006
language
English
LU publication?
yes
id
fb66f5e4-47a9-4881-96f2-7bd7d89490be (old id 414000)
date added to LUP
2016-04-01 17:06:46
date last changed
2021-06-01 04:50:31
@article{fb66f5e4-47a9-4881-96f2-7bd7d89490be,
  abstract     = {Complement, which bridges innate and adaptive immune responses as well as Immoral and cell-mediated immunity, is antiviral. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a lytic cycle protein called KSHV complement control protein (KCP) that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases. These complement regulatory activities require the short consensus repeat (SCR) motifs, of which KCP has four (SCRs 1 to 4). We found that in addition to KCP being expressed on the surfaces of experimentally infected endothelial cells, it is associated with the envelope of purified KSHV virions, potentially protecting them from complement-mediated immunity. Furthermore, recombinant KCP binds heparin, an analogue of the known KSHV cell attachment receptor heparan sulfate, facilitating infection. Treating virus with an anti-KCP monoclonal antibody (MAb), BSF8, inhibited KSHV infection of cells by 35%. Epitope mapping of MAb BSF8 revealed that it binds within SCR domains 1 and 2, also the region of the protein involved in heparin binding. This MAb strongly inhibited classical C3 convertase decay acceleration by KCP and cofactor activity for C4b cleavage but not CA cleavage. Our data suggest similar topological requirements for cell binding by KSHV, heparin binding, and regulation of C4b-containing C3 convertases but not for factor I-mediated cleavage of C3b. Importantly, they suggest KCP confers at least two functions on the virion: cell binding with concomitant infection and immune evasion.},
  author       = {Spiller, OB and Mark, Linda and Blue, CE and Proctor, DG and Aitken, JA and Blom, Anna and Blackbourn, DJ},
  issn         = {1098-5514},
  language     = {eng},
  number       = {8},
  pages        = {4068--4078},
  publisher    = {American Society for Microbiology},
  series       = {Journal of Virology},
  title        = {Dissecting the regions of virion-associated Kaposi's sarcoma-associated herpesvirus complement control protein required for complement regulation and cell binding},
  url          = {http://dx.doi.org/10.1128/JVI.80.8.4068-4078.2006},
  doi          = {10.1128/JVI.80.8.4068-4078.2006},
  volume       = {80},
  year         = {2006},
}