title: HIV-1 gp120 mannoses induce immunosuppressive responses from dendritic cells.
abstract: The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is a vaccine immunogen that can signal via several cell surface receptors. To investigate whether receptor biology could influence immune responses to gp120, we studied its interaction with human, monocyte-derived dendritic cells (MDDCs) in vitro. Gp120 from the HIV-1 strain JR-FL induced IL-10 expression in MDDCs from 62% of donors, via a mannose C-type lectin receptor(s) (MCLR). Gp120 from the strain LAI was also an IL-10 inducer, but gp120 from the strain KNH1144 was not. The mannose-binding protein cyanovirin-N, the 2G12 mAb to a mannose-dependent gp120 epitope, and MCLR-specific mAbs inhibited IL-10 expression, as did enzymatic removal of gp120 mannose moieties, whereas inhibitors of signaling via CD4, CCR5, or CXCR4 were ineffective. Gp120-stimulated IL-10 production correlated with DC-SIGN expression on the cells, and involved the ERK signaling pathway. Gp120-treated MDDCs also responded poorly to maturation stimuli by up-regulating activation markers inefficiently and stimulating allogeneic T cell proliferation only weakly. These adverse reactions to gp120 were MCLR-dependent but independent of IL-10 production. Since such mechanisms might suppress immune responses to Env-containing vaccines, demannosylation may be a way to improve the immunogenicity of gp120 or gp140 proteins.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Meimei
authors.initials: M
authors.lastname: Shan
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Banerjee
authors.forename: Antu K
authors.initials: AK
authors.lastname: Dey
authors.forename: Sai Prasad N
authors.initials: SP
authors.lastname: Iyer
authors.forename: Robert
authors.initials: R
authors.lastname: Dionisio
authors.forename: Dustin
authors.initials: D
authors.lastname: Charles
authors.forename: Lila
authors.initials: L
authors.lastname: Campbell-Gardener
authors.forename: William C
authors.initials: WC
authors.lastname: Olson
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008358:Mannose / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; C514793:gp120 protein, Human immunodeficiency virus 1; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D008358:Mannose