HCMV Reprogramming of Infected Monocyte Survival and Differentiation: A Goldilocks Phenomenon

Abstract

The wide range of disease pathologies seen in multiple organ sites associated with human cytomegalovirus (HCMV) infection results from the systemic hematogenous dissemination of the virus, which is mediated predominately by infected monocytes. In addition to their role in viral spread, infected monocytes are also known to play a key role in viral latency and life-long persistence. However, in order to utilize infected monocytes for viral spread and persistence, HCMV must overcome a number of monocyte biological hurdles, including their naturally short lifespan and their inability to support viral gene expression and replication. Our laboratory has shown that HCMV is able to manipulate the biology of infected monocytes in order to overcome these biological hurdles by inducing the survival and differentiation of infected monocytes into long-lived macrophages capable of supporting viral gene expression and replication. In this current review, we describe the unique aspects of how HCMV promotes monocyte survival and differentiation by inducing a “finely-tuned” macrophage cell type following infection. Specifically, we describe the induction of a uniquely polarized macrophage subset from infected monocytes, which we argue is the ideal cellular environment for the initiation of viral gene expression and replication and, ultimately, viral spread and persistence within the infected host.

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

“…We infected cells with HCMV (TB40/E) (24) and conducted time course experiments, extracting the nuclear fraction and performing PCR at each time point indicated. Consistent with previously reported data (21,22), we detected HCMV DNA in the nucleus of fibroblasts beginning at 30 min postinfection (mpi) (Fig. 1A).…”

“…In summary, we previously found that signaling initiated during HCMV binding to monocytes through EGFR and integrins triggers specific biological changes, such as enhanced survival (20) and accelerated differentiation (22), and now report that the signal derived from integrin engagement by gH/gL/UL128-131 plays a key role in HCMV nuclear translocation in infected monocytes. Our data suggest that this initial receptor-ligand engagement and the magnitude of the integrin signaling dictate the early entry steps, productive infection via appropriate trafficking, and degradation of the viral particle in late endosomes.…”

“…Understanding how HCMV overcomes these biological barriers following infection may provide clues to the underlying causes of HCMV pathogenesis and persistence. Our laboratory has provided molecular evidence for how HCMV evolved to deal with these biological barriers (16)(17)(18)(19)(20)(21)(22).We have shown that the biological changes in HCMV-infected monocytes are triggered by the binding of gB to EGFR (19) and binding of the gH/gL/UL128-131 complex to β1 and β3 integrins (7, 18). These receptor-ligand interactions trigger the EGFR and integrin signaling cascades, promoting enhanced motility and viral entry into monocytes (16,19).…”

“…Understanding how HCMV overcomes these biological barriers following infection may provide clues to the underlying causes of HCMV pathogenesis and persistence. Our laboratory has provided molecular evidence for how HCMV evolved to deal with these biological barriers (16)(17)(18)(19)(20)(21)(22).…”

“…Along with promoting viral attachment and enhanced motility and viral entry (16), the gH/gL/UL128-131 complex, through engagement and activation of β1 and β3 integrins, is responsible for the up-regulation of Bcl-2 that combats the later antiviral proapoptotic response and extends HCMV-infected monocyte survival (21). Although the gB/EGFR and gH/gL/UL128-131 complex/integrin receptor-ligand interactions can focus on and drive related cellular processes, they operate through distinct mechanisms (16,19,22).…”