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: Rada Ellegård, Elisa Crisci, Adam Burgener, Christopher Sjöwall, Kenzie Birse, Garrett Westmacott, Jorma Hinkula, Jeffrey D Lifson, Marie Larsson
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 9 Pg. 4590-601 (Nov 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25252956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Interferon Regulatory Factor-1
• Interferon Regulatory Factor-3
• Macrophage-1 Antigen
• NF-kappa B
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Messenger
• Toll-Like Receptor 8
• Complement System Proteins
• lyn protein-tyrosine kinase
• src-Family Kinases
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Complement System Proteins (immunology)
• Dendritic Cells (immunology, metabolism, virology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Profiling
• HIV Infections (genetics, immunology, metabolism)
• HIV-1 (immunology)
• Humans
• Immunity, Innate (genetics)
• Inflammation (genetics, immunology, metabolism)
• Interferon Regulatory Factor-1 (metabolism)
• Interferon Regulatory Factor-3 (metabolism)
• Macrophage-1 Antigen (metabolism)
• Models, Biological
• NF-kappa B (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Protein Transport
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• Toll-Like Receptor 8 (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• src-Family Kinases (metabolism)