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*
Department of Medicine, Infectious Diseases Division and Department of Pathology and
Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
Department of Biochemistry, University of Texas Health Center, Tyler, TX 75708
The envelope surface glycoprotein C (gC) of HSV-1 interferes with
the complement cascade by binding C3 and activation products C3b, iC3b,
and C3c, and by blocking the interaction of C5 and properdin with C3b.
Wild-type HSV-1 is resistant to Ab-independent complement
neutralization; however, HSV-1 mutant virus lacking gC is highly
susceptible to complement resulting in 
100-fold reduction in virus
titer. We evaluated the mechanisms by which complement inhibits HSV-1
gC null virus to better understand how gC protects against
complement-mediated neutralization. C8-depleted serum prepared from an
HSV-1 and -2 Ab-negative donor neutralized gC null virus comparable to
complement-intact serum, indicating that C8 and terminal lytic activity
are not required. In contrast, C5-depleted serum from the same donor
failed to neutralize gC null virus, supporting a requirement for C5.
EDTA-treated serum did not neutralize gC null virus, indicating that
complement activation is required. Factor D-depleted and C6-depleted
sera neutralized virus, suggesting that the alternative complement
pathway and complement components beyond C5 are not required.
Complement did not aggregate virus or block attachment to cells.
However, complement inhibited infection before early viral gene
expression, indicating that complement affects one or more of the
following steps in virus replication: virus entry, uncoating, DNA
transport to the nucleus, or immediate early gene expression.
Therefore, in the absence of gC, HSV-1 is readily inhibited by
complement by a C5-dependent mechanism that does not require viral
lysis, aggregation, or blocking virus
attachment.
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