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Journal of Virology, September 1999, p. 7658-7670, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Murine Gammaherpesvirus 68 Encodes a Functional Regulator of Complement Activation

Sharookh B. Kapadia,1 Hector Molina,2,3 Victor van Berkel,1 Samuel H. Speck,1,* and Herbert W. Virgin IV1,*

Center for Immunology, Departments of Pathology and Molecular Microbiology,1 and Departments of Medicine and Pathology,2 Washington University School of Medicine, St. Louis, Missouri 63110, and Veterans Administration Medical Center, St. Louis, Missouri 631063

Received 3 March 1999/Accepted 26 May 1999

Sequence analysis of the murine gammaherpesvirus 68 (gamma HV68) genome revealed an open reading frame (gene 4) which is homologous to a family of proteins known as the regulators of complement activation (RCA proteins) (H. W. Virgin, P. Latreille, P. Wamsley, K. Hallsworth, K. E. Weck, A. J. Dal Canto, and S. H. Speck, J. Virol. 71:5894-5904, 1997). The predicted gene 4 product has homology to other virally encoded RCA homologs, as well as to the complement-regulatory proteins decay-accelerating factor and membrane cofactor protein. Analyses by Northern blotting and rapid amplification of cDNA ends revealed that gene 4 is transcribed as a 5.2-kb bicistronic transcript of the late kinetic class. Three gamma HV68 RCA protein isoforms (60 to 65 kDa, 50 to 55 kDa, and 40 to 45 kDa) were detected by Western blotting of infected murine NIH 3T12 fibroblast cells. A soluble 40- to 45-kDa isoform was detected in the supernatants of virally infected cells. Flow cytometric analysis revealed that the gamma HV68 RCA protein was expressed on the surfaces of infected cells. Supernatants from virally infected cells contained an activity that inhibited murine complement activation as measured by inhibition of C3 deposition on activated zymosan particles. Recombinant gamma HV68 RCA protein, containing the four conserved short consensus repeats, inhibited murine C3 deposition on zymosan via both classical and alternative pathways and inhibited deposition of human C3 on activated zymosan particles. Expression of this inhibitor of complement activation, both at the cell surface and in the fluid phase, may be important for gamma HV68 pathogenesis via the inhibition of innate and adaptive immunity.

* Corresponding author. Mailing address: Center for Immunology, Departments of Pathology and Molecular Microbiology, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, MO 63110. Phone for Herbert W. Virgin, IV: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu. Phone for Samuel H. Speck: (314) 362-0367. Fax: (314) 362-4096. E-mail: speck{at}pathbox.wustl.edu.

Journal of Virology, September 1999, p. 7658-7670, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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