The survival of monocytes infected by human cytomegalovirus is dependent on a unique signalsome induced during entry.

HCMV infection of immunocompromised individuals often leads to multi-system organ failure. The development of multi-system organ failure is dependent on the ability of HCMV to spread to peripheral organs, which is mediated by blood monocytes. We have previously shown HCMV to extend the short 48hr lifespan of monocytes. Mechanistically, HCMV upregulated cellular myeloid leukemia sequence 1 (Mcl-1) and heat shock protein 27 (HSP27), to block the proteolytic cleavages necessary for the formation of active caspase 3. We now show that, compared to other myeloid survival factors, HCMV infection more efficiently upregulates Mcl-1 and the only survival factor to rapidly induce HSP27. These observations, suggest a unique virus specific mechanism of induction; thus, we examined receptor: ligand signaling events, since viral anti-apoptotic proteins are not expressed until differentiation into macrophages is complete. We determined that HCMV-induced EGFR/PI3K/AKT signaling increased the transcription of both Mcl-1 and HSP27. Yet, protein expression of Mcl-1 and HSP27 is increased via the gH/aVb3/src and the gB/EGFR pathways, respectively. To address this discrepancy between transcripts and protein we evaluated the effects of HCMV on the translation of Mcl-1 and HSP27. Indeed, we found, in contrast to myeloid survival factors, HCMV stimulated the translation of Mcl-1 and HSP27. Overall, these data indicate that inhibition of apoptosis by HCMV is through the unique signaling regulation of Mcl-1 and HSP27; ensuring short-lived monocyte survival past the normal 48hr viability checkpoint, a key event necessary for viral dissemination.