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.
Highlights
Following the advent and the rapid expansion of human cytomegalovirus (HCMV) infections caused by both human immunodeficiency virus (HIV) epidemics, as well as the administration of immunosuppressive drugs required for organ and stem cell transplantation, the rate of disseminated HCMV infections reached a peak, giving rise to the study of their pathogenesis
Based on the observation that this was a hallmark of all laboratory-adapted HCMV strains, as well as fibroblast-passaged clinical isolates, we proposed endothelial cell- and leuko-tropism as surrogate markers of pathogenicity for HCMV virulent strains, while their absence should be considered a marker of virus attenuation [33]
It is likely that both trimer complex (TC) and pentamer complex (PC) are required for infection of epithelial cells/endothelial cells, but the emerging hypothesis is that the gH/gL component of both TC and PC serves as the first activator of the fusogenic activity of gB through a conformational change in HCMV gL occurring upon receptor binding [77], similar to that reported for Epstein-Barr virus gL [78,79]
Summary
Following the advent and the rapid expansion of human cytomegalovirus (HCMV) infections caused by both human immunodeficiency virus (HIV) epidemics, as well as the administration of immunosuppressive drugs required for organ and stem cell transplantation, the rate of disseminated HCMV infections reached a peak, giving rise to the study of their pathogenesis. Using a double-staining method, including one monoclonal antibody (mAb) staining the cell type and another staining the HCMV gene products, the cells most frequently identified as permissive to HCMV in vivo in different organs of patients with disseminated infection were found to be endothelial cells, epithelial cells, human fibroblasts, and smooth muscle cells. Polymorphonuclear leukocytes (PMNLs) do not seem to be permissive to HCMV replication, but can transport the virus passively [4]. One important cellular reservoir of latent HCMV is CD34+ hematopoietic progenitor cells resident in the bone marrow [5]
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