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Interaction of complement with human cytomegalovirus

University of British Columbia

In the absence of specific anti-human cytomegalovirus (HCMV) antibodies, complement has a negligible neutralizing effect on the virions. Under these conditions, the presence of activated C3 fragments, but not C9, were found on the HCMV virions. There are no known viral complement inhibitors encoded in the HCMV genome, but the presence of host-encoded complement inhibitors, CD55, CD46, and CD59, on the HCMV virions may explain the virion’s ability to regulate complement. In the presence of anti-HCMV antibodies, complement enhanced the neutralizing ability of the immunoglobulins by 2-3 fold. Complement activation in the presence of antibodies occurred primarily by the classical complement activation pathway and was complete, as assessed by the presence of C9. CD55 (decay-accelerating factor) and CD46 (membrane co-factor protein) regulate complement at the level of C3 and belong the regulators of complement activation (RCA) gene cluster. CD59 regulates complement at the level of the terminal lytic pathway and does not belong to the RCA gene cluster. HCMV infection of fibroblasts and glioblastoma cells resulted in a 3-8 fold increase in the expression of CD55 and CD46 by 72 h p.i., but infection with herpes simplex virus or adenovirus had no effect. An increase in C3 convertase regulation was also found on the HCMV-infected cells using a purified complement component assay. By contrast, CD59 expression was decreased on HCMV-infected cells by 50% by 72 h p.i., similar to the decrease observed for HLA class I. CD55 expression was increased in HCMV-infected cells at the level of protein, mRNA, and transcription of the gene as assessed by using a variety of techniques. Similarly, the levels of CD59 mRNA decreased in the HCMV infected cells, paralleling the observations for protein expression, but radiolabel pulse-chase analysis identified a decreased CD59 protein survival. Indirect evidence suggested that the immediate early or early genes from HCMV were responsible for the altered expression of host complement inhibitors, but CD55 promoter activity and protein expression were unaffected by the presence of isolated HCMV immediate early genes.

Thesis/Dissertation

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2009-06-11

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http://hdl.handle.net/2429/8968

Pathology

University of British Columbia

UBCV

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