title: Inhibition of two temporal phases of HIV-1 transfer from primary Langerhans cells to T cells: the role of langerin.
abstract: Epidermal Langerhans cells (eLCs) uniquely express the C-type lectin receptor langerin in addition to the HIV entry receptors CD4 and CCR5. They are among the first target cells to encounter HIV in the anogenital stratified squamous mucosa during sexual transmission. Previous reports on the mechanism of HIV transfer to T cells and the role of langerin have been contradictory. In this study, we examined HIV replication and langerin-mediated viral transfer by authentic immature eLCs and model Mutz-3 LCs. eLCs were productively infected with HIV, whereas Mutz-3 LCs were not susceptible because of a lack of CCR5 expression. Two successive phases of HIV viral transfer to T cells via cave/vesicular trafficking and de novo replication were observed with eLCs as previously described in monocyte-derived or blood dendritic cells, but only first phase transfer was observed with Mutz-3 LCs. Langerin was expressed as trimers after cross-linking on the cell surface of Mutz-3 LCs and in this form preferentially bound HIV envelope protein gp140 and whole HIV particles via the carbohydrate recognition domain (CRD). Both phases of HIV transfer from eLCs to T cells were inhibited when eLCs were pretreated with a mAb to langerin CRD or when HIV was pretreated with a soluble langerin trimeric extracellular domain or by a CRD homolog. However, the langerin homolog did not inhibit direct HIV infection of T cells. These two novel soluble langerin inhibitors could be developed to prevent HIV uptake, infection, and subsequent transfer to T cells during early stages of infection.
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia;
authors: Najla
authors: N
authors: Nasr
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia;
authors: Joey
authors: J
authors: Lai
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia;
authors: Rachel A
authors: RA
authors: Botting
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia;
authors: Sarah K
authors: SK
authors: Mercier
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia;
authors: Andrew N
authors: AN
authors: Harman
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia;
authors: Min
authors: M
authors: Kim
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia;
authors: Stuart
authors: S
authors: Turville
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors: Rob J
authors: RJ
authors: Center
authors: Apollo Life Sciences Pty, Beaconsfield, New South Wales 2015, Australia;
authors: Teresa
authors: T
authors: Domagala
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia; and.
authors: Paul R
authors: PR
authors: Gorry
authors: Sydney Institute of Plastic and Reconstructive Surgery, Chatswood, New South Wales 2067, Australia.
authors: Norman
authors: N
authors: Olbourne
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales 2145, Australia; University of Sydney, Sydney, New South Wales 2000, Australia; tony.cunningham@sydney.edu.au.
authors: Anthony L
authors: AL
authors: Cunningham
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D001692:Biological Transport / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000276:immunology*; D037241:Mannose-Binding Lectins / Q000037:antagonists & inhibitors / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C121916:CD207 protein, human; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1