Ar. Chaudhuri et al., Apoptosis induced by human cytomegalovirus infection can be enhanced by cytokines to limit the spread of virus, EXP HEMATOL, 27(7), 1999, pp. 1194-1203
Fas-mediated apoptosis is one of the immune effector pathways leading to th
e elimination of virus infected cells. In vivo, apoptotic signals are deliv
ered to virus infected cells by Fas-L and other cytokines secreted by speci
fic T lymphocytes. Cellular immune response appears to be essential in prev
ention of human cytomegalovirus (HCMV) disease. We have hypothesized that H
CMV infection might directly or indirectly result in upregulation of Fas re
ceptor and in the presence of Fas ligand, lead to apoptosis of infected cel
ls. We show that infection of human fibroblasts with HCMV is associated wit
h up-modulation of Fas-R process that could be further potentiated by inter
feron (IFN-gamma). Using DNA agarose gel electrophoresis, terminal dideoxy
transferase reaction, and annexin assay, we demonstrated that in a producti
ve HCMV infection of human fibroblasts, loss of cell viability was not only
due to virus-mediated cell lysis but also to due to apoptosis, IFN-gamma i
nduced relative HCMV resistance and prevented loss in cell viability. In co
ntrast, anti-Fas monoclonal antibody CH11, serving as Fas agonist, resulted
in an accelerated loss in viability of infected cells, IFN-gamma in combin
ation with CH11 further increased the rate of apoptosis and compared to cul
tures with CH11 only, this effect was not restricted to only infected cells
. While IFN-gamma did not affect the number of cells expressing immediate e
arly antigen, it markedly reduced structural protein expression. IFN-gamma
in combination with CH11, decreased the expression of HCMV matrix protein p
p65, reduced the amount of HCMV DNA and infectious virus produced, Our resu
lts are consistent with the theory that cells infected with HCMV can be eli
minated by immune effector cells via Fas-mediated apoptosis, IFN-gamma, in
addition to its intrinsic antiviral activity, primes HCMV infected cells to
the action of Fas ligand and Fas-mediated apoptosis. (C) 1999 Internationa
l Society for Experimental Hematology. Published by Elsevier Science Inc.