Abstract
Sustained phosphotinositide3-kinase (PI3K) signaling is critical to the maintenance of alpha and beta herpesvirus latency. We have previously shown that the beta-herpesvirus, human cytomegalovirus (CMV), regulates epidermal growth factor receptor (EGFR), upstream of PI3K, to control states of latency and reactivation. How signaling downstream of EGFR is regulated and how this impacts CMV infection and latency is not fully understood. We demonstrate that CMV downregulates EGFR early in the productive infection, which blunts the activation of EGFR and its downstream pathways in response to stimuli. However, CMV infection sustains basal levels of EGFR and downstream pathway activity in the context of latency in CD34+ hematopoietic progenitor cells (HPCs). Inhibition of MEK/ERK, STAT or PI3K/AKT pathways downstream of EGFR increases viral reactivation from latently infected CD34+ HPCs, defining a role for these pathways in latency. We hypothesized that CMV modulation of EGFR signaling might impact viral transcription important to latency. Indeed, EGF-stimulation increased expression of the UL138 latency gene, but not immediate early or early viral genes, suggesting that EGFR signaling promotes latent gene expression. The early growth response-1 (EGR1) transcription factor is induced downstream of EGFR signaling through the MEK/ERK pathway and is important for the maintenance of hematopoietic stemness. We demonstrate that EGR1 binds the viral genome upstream of UL138 and is sufficient to promote UL138 expression. Further, disruption of EGR1 binding upstream of UL138 prevents the establishment of latency in CD34+ HPCs. Our results indicate a model whereby UL138 modulation of EGFR signaling feeds back to promote UL138 gene expression and suppression of replication for latency. By this mechanism, the virus has hardwired itself into host cell biology to sense and respond to changes in homeostatic host cell signaling.
Highlights
The mechanisms by which herpesviruses persist through the establishment of a quiescent infection, known as latency, and reactivate for continued transmission are incompletely defined
We have shown that human cytomegalovirus regulates epidermal growth factor receptor (EGFR) levels and trafficking and that sustained EGFR or downstream PI3K signaling is a requirement for viral latency
We show that EGFR signaling through MEK/ ERK pathway induces the host early growth response factor 1 (EGR1) transcription factor that is highly expressed in hematopoietic stem cells and necessary for the maintenance of hematopoietic stemness
Summary
The mechanisms by which herpesviruses persist through the establishment of a quiescent infection, known as latency, and reactivate for continued transmission are incompletely defined. It is known that herpesviruses “sense and respond" to changes in host cell signaling, such as that associated with stress and differentiation, to modulate the “decisions” to maintain latency or to reactivate. The molecular underpinnings of how these cellular signals induce changes in chromatin and viral gene expression are less well defined. During infection of an immunocompetent host, CMV has a protracted acute phase and establishes a life-long latent infection, which is marked by sporadic subclinical reactivation events. Understanding the molecular mechanisms that define and control the latent CMV infection is critical for the development of novel strategies to target the latent infection
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
