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.

The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression

“…These complement receptors play an important role in eliminating complement-opsonized pathogens and apoptotic particles and contribute to cell homeostasis during tissue remodeling (69). Their role as important modulators of the host inflammatory response is highlighted by the fact that they are exploited by pathogenic bacteria and viruses to potentiate host cell invasion, hijacking signaling downstream of the receptors to reduce inflammatory cytokine production (70,71). In a similar fashion, activation of CR3 in dendritic cells during apoptotic cell clearance promotes intracellular tolerogenic signals (72).…”

Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1

“…(9)(10)(11)(12)23). In addition, we recently found that the inflammatory and antiviral responses induced by HIV in immature DCs are decreased when the virus is complement opsonized, resulting in enhanced infection (13). In this study, we show that the interaction between immature DCs and CI-HIV results in decreased production of chemokines and the ability to attract other immune cells, particularly NK cells.…”

“…We have previously shown that C-HIV inhibits induction of inflammatory cytokines in DCs via CR3 interaction (13), and we show that this mechanism also affected the release of chemotactic chemokines and thereby the attraction of immune cells. In a recent SIV study, it was shown that a surprisingly low number of NK cells migrated to the site of infection after vaginal challenge, and the NK cells that did migrate lacked markers associated with activation and cytotoxicity (57).…”

“…Although the presence of complement generally protects the body from pathogens, it increases both direct HIV infection of immature DCs and DC mediated HIV trans infection of T cells (9)(10)(11)(12). We recently found that the elevated infection of DCs induced by complement-opsonized HIV is due to complementmediated suppression of antiviral and inflammatory responses (13).…”

A Novel Role for the Receptor of the Complement Cleavage Fragment C5a, C5aR1, in CCR5-Mediated Entry of HIV into Macrophages

“…CR1 is widely expressed on erythrocytes and C3b-coated HIV uses CR1 on erythrocytes to spread into tissues, where degradation of C3b into iC3b and C3d,g allows the virus to infect a wide spectrum of CR2-, CR3-, and CR4-expressing cells such as B cells, macrophages, and dendritic cells (DCs). [5][6][7] B cells that bind C3d,g-coated virus particles may disseminate and transmit infectious virus to activated T cells. 8 Furthermore, follicular DCs that bind C3d-opsonized HIV through CR2 provide an important extracellular HIV reservoir in germinal centers.…”