title: DC-SIGN increases the affinity of HIV-1 envelope glycoprotein interaction with CD4.
abstract: Mannose-binding C-type lectin receptors, expressed on Langerhans cells and subepithelial dendritic cells (DCs) of cervico-vaginal tissues, play an important role in HIV-1 capture and subsequent dissemination to lymph nodes. DC-SIGN has been implicated in both productive infection of DCs and the DC-mediated trans infection of CD4(+) T cells that occurs in the absence of replication. However, the molecular events that underlie this efficient transmission have not been fully defined. In this study, we have examined the effect of the extracellular domains of DC-SIGN and Langerin on the stability of the interaction of the HIV-1 envelope glycoprotein with CD4 and also on replication in permissive cells. Surface plasmon resonance analysis showed that DC-SIGN increases the binding affinity of trimeric gp140 envelope glycoproteins to CD4. In contrast, Langerin had no effect on the stability of the gp140:CD4 complex. In vitro infection experiments to compare DC-SIGN enhancement of CD4-dependent and CD4-independent strains demonstrated significantly lower enhancement of the CD4-independent strain. In addition DC-SIGN increased the relative rate of infection of the CD4-dependent strain but had no effect on the CD4-independent strain. DC-SIGN binding to the HIV envelope protein effectively increases exposure of the CD4 binding site, which in turn contributes to enhancement of infection.
authors.affiliation: King's College London, Dental Institute, Oral Immunology, Tower Wing, Guy's Hospital, London, United Kingdom.
authors.forename: Karolin
authors.initials: K
authors.lastname: Hijazi
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wang
authors.forename: Carlo
authors.initials: C
authors.lastname: Scala
authors.forename: Simon
authors.initials: S
authors.lastname: Jeffs
authors.forename: Colin
authors.initials: C
authors.lastname: Longstaff
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieh
authors.forename: Beth
authors.initials: B
authors.lastname: Haggarty
authors.forename: Guido
authors.initials: G
authors.lastname: Vanham
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Ian M
authors.initials: IM
authors.lastname: Jones
authors.forename: James
authors.initials: J
authors.lastname: Hoxie
authors.forename: Robin
authors.initials: R
authors.lastname: Shattock
authors.forename: Charles G
authors.initials: CG
authors.lastname: Kelly
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D037181:Lectins, C-Type / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D020349:Surface Plasmon Resonance; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C097729:gp140 envelope protein, Human immunodeficiency virus 1