FIG 7.

Model for early HCMV infection of CD34⁺ HPCs. (Left) Various treatments used in this study to investigate HCMV-induced EGFR signaling in CD34⁺ HPCs. Pretreatment with anti-EGFR blocking antibodies was used to block HCMV-EGFR engagement at the cell surface and any direct signaling downstream of that specific engagement. Pretreatment with the signaling inhibitors AG1478 (EGFRK inhibitor) and LY294002 (PI3K inhibitor) was used to attenuate HCMV-induced molecular signaling associated with the viral binding and entry events. AG1478 was also used at 30 mpi or at 4 hpi to attenuate EGFR signaling after viral entry and trafficking commenced. (Right) Summary of our findings from this investigation. HCMV enters CD34⁺ HPCs via engagement of EGFR on the cell surface. The entry event is dependent upon both EGFRK and downstream PI3K signaling. HCMV de-envelopment occurs within 1 and 4 hpi, with nuclear translocation of the viral DNA occurring between 4 and 8 hpi. Both de-envelopment and delivery of HCMV DNA to the nucleus are enhanced by EGFR signaling. Once in the nucleus, HCMV initiates the appropriate cell-type-specific viral transcription program and also alters the transcription of the cellular genes that favor infection of CD34⁺ HPCs. EGFR signaling plays a role in shaping the induced viral and cellular transcriptional profiles during the initial stages of infection.