title: CD4 coexpression regulates DC-SIGN-mediated transmission of human immunodeficiency virus type 1.
abstract: Dendritic cells (DCs) potently stimulate the cell-cell transmission of human immunodeficiency virus type 1 (HIV-1). However, the mechanisms that underlie DC transmission of HIV-1 to CD4(+) T cells are not fully understood. DC-SIGN, a C-type lectin, efficiently promotes HIV-1 trans infection. DC-SIGN is expressed in monocyte-derived DCs (MDDCs), macrophage subsets, activated B lymphocytes, and various mucosal tissues. MDDC-mediated HIV-1 transmission to CD4(+) T cells involves DC-SIGN-dependent and -independent mechanisms. DC-SIGN transmission of HIV-1 depends on the donor cell type. HIV-1 Nef can upregulate DC-SIGN expression and promote DC-T-cell clustering and HIV-1 spread. Nef also downregulates CD4 expression; however, the effect of the CD4 downmodulation on DC-mediated HIV-1 transmission has not been examined. Here, we report that CD4 expression levels correlate with inefficient HIV-1 transmission by monocytic cells expressing DC-SIGN. Expression of CD4 on Raji B cells strongly impaired DC-SIGN-mediated HIV-1 transmission to T cells. By contrast, enhanced HIV-1 transmission was observed when CD4 molecules on MDDCs and DC-SIGN-CD4-expressing cell lines were blocked with specific antibodies. Coexpression of CD4 and DC-SIGN in Raji cells promoted the internalization and intracellular retention of HIV-1. Interestingly, internalized HIV-1 particles were sorted and confined to late endosomal compartments that were positive for CD63 and CD81. Furthermore, in HIV-1-infected MDDCs, significant downregulation of CD4 by Nef expression correlated with enhanced viral transmission. These results suggest that CD4, which is present at various levels in DC-SIGN-positive primary cells, is a key regulator of HIV-1 transmission.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, BSB 203, Milwaukee, WI 53226, USA.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Wang
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Janas
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Olson
authors.forename: Vineet N
authors.initials: VN
authors.lastname: KewalRamani
authors.forename: Li
authors.initials: L
authors.lastname: Wu
mesh_terms: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D015693:Gene Products, nef / Q000502:physiology; D015754:Genes, nef; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D037181:Lectins, C-Type / Q000235:genetics / Q000502:physiology*; D009000:Monocytes / Q000276:immunology / Q000821:virology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization; D054311:nef Gene Products, Human Immunodeficiency Virus; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D015693:Gene Products, nef; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C514837:nef protein, Human immunodeficiency virus 1