Complement regulation by Kaposi's sarcoma-associated herpesvirus ORF4 protein

O. Brad Spiller, Mairi Robinson, Elizabeth O'Donnell, Steven Milligan, B. Paul Morgan, Andrew J. Davison, David J. Blackbourn*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)


Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with three types of human tumor: Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. The virus encodes a number of proteins that participate in disrupting the immune response, one of which was predicted by sequence analysis to be encoded by open reading frame 4 (ORF4). The predicted ORF4 protein shares homology with cellular proteins referred to as regulators of complement activation. In the present study, the transcription profile of the ORF4 gene was characterized, revealing that it encodes at least three transcripts, by alternative splicing mechanisms, and three protein isoforms. Functional studies revealed that each ORF4 protein isoform inhibits complement and retains a C-terminal transmembrane domain. Consistent with the complement-regulating activity, we propose to name the proteins encoded by the ORF4 gene collectively as KSHV complement control protein (KCP). KSHV ORF4 is the most complex alternatively spliced gene encoding a viral complement regulator described to date. KCP inhibits the complement component of the innate immune response, thereby possibly contributing to the in vivo persistence and pathogenesis of this virus.

Original languageEnglish
Pages (from-to)592-599
Number of pages8
JournalJournal of Virology
Issue number1
Publication statusPublished - Jan 2003

Bibliographical note

We thank Charles Cunningham for performing the 5′-RACE PCR, Maeve MacLeod for the IFA, and Jay A. Levy for critical reading of the manuscript.

This work was supported in part by grants from the Wellcome Trust (059008/Z/99/Z to D.J.B. and 061150/Z/00/Z to O.B.S.), the Cunningham Trust (ACC/KM CT to D.J.B.), The Royal Society (574006.G503/21709/SM to D.J.B.), and Cancer Research UK (C7934 to O.B.S. and D.J.B.)


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