title: Human cytomegalovirus entry into dendritic cells occurs via a macropinocytosis-like pathway in a pH-independent and cholesterol-dependent manner.
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.
authors.affiliation: Unité Mixte de Recherche_S 1064, ex643, Institut National de la Santé et de la Recherche Médicale, Institute for Transplantation/Urology and Nephrology, Nantes, France. franck.halary@univ-nantes.fr
authors.forename: Fabienne
authors.initials: F
authors.lastname: Haspot
authors.forename: Amélie
authors.initials: A
authors.lastname: Lavault
authors.forename: Christian
authors.initials: C
authors.lastname: Sinzger
authors.forename: Kerstin
authors.initials: K
authors.lastname: Laib Sampaio
authors.forename: York-Dieter
authors.initials: YD
authors.lastname: Stierhof
authors.forename: Paul
authors.initials: P
authors.lastname: Pilet
authors.forename: Céline
authors.initials: C
authors.lastname: Bressolette-Bodin
authors.forename: Franck
authors.initials: F
authors.lastname: Halary
mesh_terms: D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology*; D003587:Cytomegalovirus / Q000502:physiology*; D003713:Dendritic Cells / Q000821:virology*; D006801:Humans; D008264:Macrophages / Q000821:virology; D009000:Monocytes / Q000821:virology; D010873:Pinocytosis; D053586:Virus Internalization
chemical_list: D002784:Cholesterol