Abstract
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to infect fibroblastic, epithelial, endothelial and hematopoietic cells. Over the past ten years, several groups have provided direct evidence that dendritic cells (DCs) fully support the HCMV lytic cycle. We previously demonstrated that the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) has a prominent role in the docking of HCMV on monocyte-derived DCs (MDDCs). The DC-SIGN/HCMV interaction was demonstrated to be a crucial and early event that substantially enhanced infection in trans, i.e., from one CMV-bearing cell to another non-infected cell (or trans-infection), and rendered susceptible cells fully permissive to HCMV infection. Nevertheless, nothing is yet known about how HCMV enters MDDCs. In this study, we demonstrated that VHL/E HCMV virions (an endothelio/dendrotropic strain) are first internalized into MDDCs by a macropinocytosis-like process in an actin- and cholesterol-dependent, but pH-independent, manner. We observed the accumulation of virions in large uncoated vesicles with endosomal features, and the virions remained as intact particles that retained infectious potential for several hours. This trans-infection property was specific to MDDCs because monocyte-derived macrophages or monocytes from the same donor were unable to allow the accumulation of and the subsequent transmission of the virus. Together, these data allowed us to delineate the early mechanisms of the internalization and entry of an endothelio/dendrotropic HCMV strain into human MDDCs and to propose that DCs can serve as a "Trojan horse" to convey CMV from entry sites to other locations that may favor the occurrence of either latency or acute infection.
Highlights
Human cytomegalovirus (HCMV) can infect virtually any target cell of human origin; viral transmission, systemic spread and proliferation occur in different cell types: epithelial cells, endothelial and hematopoietic cells and fibroblasts and smooth muscle cells, respectively
Because dendritic cells have been postulated to have a role in the systemic spread of the virus, we aimed to characterize the mechanisms of HCMV internalization/entry into monocyte-derived DCs (MDDCs)
We are aware that additional experiments using the 3D focused ion beam-scanning electron microscopy would be required to definitely conclude on the type of cellular structures involved in the CMV entry in MDDCs
Summary
Human cytomegalovirus (HCMV) can infect virtually any target cell of human origin; viral transmission, systemic spread and proliferation occur in different cell types: epithelial cells, endothelial and hematopoietic cells and fibroblasts and smooth muscle cells, respectively (see [1] for review). Higher avidity receptors, such as b2-microglobulin [3], HLA-B27 [4], annexin II [5], CD13 [6,7], EGFR [8] or integrins [9] have been shown to promote stable attachment but to varying degrees. Most of these receptors have been shown to play only minor roles [10,11,12] or even no role at all in HCMV capture and entry except for b1 integrins and to a lesser extent b3 integrins [13]. It appears that HCMV likely uses distinct cell surface receptors with docking or entrymediating properties, depending on the target cell
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