Human Cytomegalovirus Cell Tropism and Host Cell Receptors

Abstract

In the 1970s–1980s, a striking increase in the number of disseminated human cytomegalovirus (HCMV) infections occurred in immunosuppressed patient populations. Autopsy findings documented the in vivo disseminated infection (besides fibroblasts) of epithelial cells, endothelial cells, and polymorphonuclear leukocytes. As a result, multiple diagnostic assays, such as quantification of HCMV antigenemia (pp65), viremia (infectious virus), and DNAemia (HCMV DNA) in patient blood, were developed. In vitro experiments showed that only low passage or endothelial cell-passaged clinical isolates, and not laboratory-adapted strains, could reproduce both HCMV leuko- and endothelial cell-tropism, which were found through genetic analysis to require the three viral genes UL128, UL130, and UL131 of the HCMV UL128 locus (UL128L). Products of this locus, together with gH/gL, were shown to form the gH/gL/pUL128L pentamer complex (PC) required for infection of epithelial cells/endothelial cells, whereas gH/gL and gO form the gH/gL/gO trimer complex (TC) required for infection of all cell types. In 2016, following previous work, a receptor for the TC that mediates entry into fibroblasts was identified as PDGFRα, while in 2018, a receptor for the PC that mediates entry into endothelial/epithelial cells was identified as neuropilin2 (Nrp2). Furthermore, the olfactory receptor family member OR14I1 was recently identified as a possible additional receptor for the PC in epithelial cells. Thus, current data support two models of viral entry: (i) in fibroblasts, following interaction of PDGFRα with TC, the latter activates gB to fuse the virus envelope with the cell membrane, whereas (ii) in epithelial cells/endothelial cells, interaction of Nrp2 (and OR14I1) with PC promotes endocytosis of virus particles, followed by gB activation by gH/gL/gO (or gH/gL) and final low-pH entry into the cell.

Mass Spectrometry-Based Characterization of the Virion Proteome, Phosphoproteome, and Associated Kinase Activity of Human Cytomegalovirus

“…This protein is a component of a pentameric envelope protein complex, consisting of glycoproteins H and L, as well as pUL130 and pUL131 [58]. The pentameric complex (PC) has been shown to be important for HCMV infection of cell types such as endothelial cells and epithelial cells [58][59][60][61]. Laboratory HCMV strains are devoid of the PC because of mutations in the UL128-131 gene region.…”

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

“…Finally, late genes are expressed after viral DNA replication has commenced and encode mostly structural proteins of the capsid, tegument or envelope required for the assembly and egress of progeny virions [19][20][21]. HCMV replicates in a wide variety of differentiated cell types, and targets select types of poorly differentiated cells including myeloid progenitors for latent infection with limited viral gene expression [22][23][24][25][26]. Viral reactivation from latency is brought about by cellular differentiation and/or stimulation and contributes greatly to pathogenesis in vulnerable hosts [27][28][29].…”

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

“…It is in this environment that the discovery of an important HCMV receptor, the plateletderived growth factor receptor α (PDGFRα), has generated excitement towards the development of new therapeutics inhibiting virus-host cell attachment and entry. Two glycoprotein complexes on the HCMV surface drive broad host cell tropism [22]. A pentameric complex of glycoprotein H (gH; UL75), gL (UL115), UL128, UL130 and UL131A mediates entry into epithelial and endothelial cells [23][24][25][26][27][28], possibly through engagement of neuropilin-2 [29] or the olfactory receptor OR14I1 [30] on the host cell.…”