Abstract
Human cytomegalovirus (HCMV) is known to evade extrinsic pro-apoptotic pathways not only by downregulating cell surface expression of the death receptors TNFR1, TRAIL receptor 1 (TNFRSF10A) and TRAIL receptor 2 (TNFRSF10B), but also by impeding downstream signalling events. Fas (CD95/APO-1/TNFRSF6) also plays a prominent role in apoptotic clearance of virus-infected cells, so its fate in HCMV-infected cells needs to be addressed. Here, we show that cell surface expression of Fas was suppressed in HCMV-infected fibroblasts from 24 h onwards through the late phase of productive infection, and was dependent on de novo virus-encoded gene expression but not virus DNA replication. Significant levels of the fully glycosylated (endoglycosidase-H-resistant) Fas were retained within HCMV-infected cells throughout the infection within intracellular membranous structures. HCMV infection provided cells with a high level of protection against Fas-mediated apoptosis. Downregulation of Fas was observed with HCMV strains AD169, FIX, Merlin and TB40.
Highlights
We show that cell surface expression of Fas was suppressed in Human cytomegalovirus (HCMV)-infected fibroblasts from 24 h onwards through the late phase of productive infection, and was dependent on de novo virus-encoded gene expression but not virus DNA replication
Downregulation of Fas was observed with HCMV strains AD169, FIX, Merlin and TB40
HCMV possesses an impressive array of immunomodulatory functions that are instrumental in avoiding T cells, natural killer (NK) cells, the interferon response and apoptosis
Summary
HCMV infection provided cells with a high level of protection against Fas-mediated apoptosis. HCMV downregulates Fas were incubated with supernatants (sn) of strain Merlin-infected cells (m.o.i. 10, 72 h p.i.) from which virions had been removed using a 0.1 mm filter, or were infected with HCMV strain Merlin (m.o.i. 10, 72 h) or an equivalent c-irradiated preparation (2500 Gy) and analysed by flow cytometry for cell surface Fas expression (n53). (d) HFFF-hTERTs were infected with HCMV strains Merlin, AD169, FIX or TB40 (m.o.i. 10, 72 h) and analysed by flow cytometry for cell surface Fas expression (n¢3).
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