Aspects of the HSV-1 life cycle, such as stimulating the progression of the cell cycle in the absence of serum, may be sufficient to induce a stress response and trigger apoptosis. Both bcl2 (Bcl-2) and bcl2l1 (Bcl-xl) belong to the Bcl-2 family of apoptosis regulators that provide cellular protection from a range of harmful stimuli such as cytokine deprivation, UV-and cirradiation [37] . Bcl-2 and Bcl-xl are found in the outer mitochondrial membrane and are thought to suppress apoptosis by blocking mitochondrial outer-membrane permeabilisation through the sequestration of pro-apoptotic Bcl2 family members [38] . Given the up-regulation of four anti-apoptotic genes, birc2, birc3, bcl2 and bcl2l1, through the activation of multiple signalling pathways by entry-defective HSV-1, this establishes a role for gD binding in shifting the intracellular environment towards a more anti-apoptotic stance. . Model for glycoprotein-receptor interactions in the induction of intracellular signalling pathways by HSV-1. Glycoprotein D acts as the main signalling molecule on the surface of the HSV-1 envelope. gH interacts with a v b 3 integrins to potentially trigger the production of IFN-b, which is known to involve IRF-3 and 7 [48] . Binding by gD to HvEM may lead to the activation of TRAF molecules, which in turn stimulate the NF-kB signaling cascade. This pathway up-regulates a number of cellular genes in addition to augmenting early viral gene expression. NF-kBresponsive genes, birc2 and birc3, have an anti-apoptotic role, but paradoxically, inflammatory mediators such as ccl2 are also up-regulated. gDinduced signalling of the Jak/Stat and Jak/Src pathways also results in the differential expression of genes associated with anti-apoptosis and inflammation. The up-regulation of c-Myc could lead to a corresponding increase in cdk2, which has a role in promoting DNA replication and gene transcription during infection. It should be noted that most signalling cascades have been elucidated in non-fibroblast cells lines, so the role of specific kinases may vary in HFFs. doi:10.1371/journal.pone.0009560.g003