title: Complement opsonization of HIV-1 results in decreased antiviral and inflammatory responses in immature dendritic cells via CR3.
abstract: Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-β, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1β, IL-6, and TNF-α, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-κB pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden;
authors.forename: Rada
authors.initials: R
authors.lastname: Ellegård
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden;
authors.forename: Elisa
authors.initials: E
authors.lastname: Crisci
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada; National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada;
authors.forename: Adam
authors.initials: A
authors.lastname: Burgener
authors.affiliation: Division of Rheumatology/Autoimmunity and Immune Regulation Unit, Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sjöwall
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada; National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada;
authors.forename: Kenzie
authors.initials: K
authors.lastname: Birse
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada;
authors.forename: Garrett
authors.initials: G
authors.lastname: Westmacott
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden;
authors.forename: Jorma
authors.initials: J
authors.lastname: Hinkula
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden; marie.larsson@liu.se.
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
mesh_terms: D003165:Complement System Proteins / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D051200:Toll-Like Receptor 8; D003165:Complement System Proteins; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases