Complement Potentiates Immune Sensing of HIV-1 and Early Type I Interferon Responses

• Published in: mBio 2021-10, Vol.12 (5), p.e0240821-e0240821
• Main Authors: Posch, Wilfried, Bermejo-Jambrina, Marta, Steger, Marion, Witting, Christina, Diem, Gabriel, Hörtnagl, Paul, Hackl, Hubert, Lass-Flörl, Cornelia, Huber, Lukas A, Geijtenbeek, Teunis B H, Wilflingseder, Doris
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Complement System Proteins - immunology; Dendritic Cells - immunology; Dendritic Cells - virology; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - virology; HIV-1 - genetics; HIV-1 - immunology; Host-Microbial Interactions; Humans; Integrin alphaXbeta2 - genetics; Integrin alphaXbeta2 - immunology; Interferon Type I - genetics; Interferon Type I - immunology; Interferon-Induced Helicase, IFIH1 - genetics; Interferon-Induced Helicase, IFIH1 - immunology; Receptors, CCR5 - genetics; Receptors, CCR5 - immunology; Research Article
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mBio.02408-21

Complement-opsonized HIV-1 triggers efficient antiviral type I interferon (IFN) responses in dendritic cells (DCs), which play an important role in protective responses at the earliest stages in retroviral infection. In contrast, HIV-1 suppresses or escapes sensing by STING- and MAVS-associated sensors. Here, we identified a complement receptor-mediated sensing pathway, where DCs are activated in CCR5/RLR (RIG-I/MDA5)/MAVS/TBK1-dependent fashion. Increased fusion of complement-opsonized HIV-1 via complement receptor 4 and CCR5 leads to increased incoming HIV-1 RNA in the cytoplasm, sensed by a nonredundant cooperative effect of RIG-I and MDA5. Moreover, complement-opsonized HIV-1 down-modulated the MAVS-suppressive Raf-1/PLK1 pathway, thereby opening the antiviral recognition pathway via MAVS. This in turn was followed by MAVS aggregation and subsequent TBK1/IRF3/NF-κB activation in DCs exposed to complement- but not non-opsonized HIV-1. Our data strongly suggest that complement is important in the induction of efficient antiviral immune responses by preventing HIV-1 suppressive mechanisms as well as inducing specific cytosolic sensors. Importantly, our study highlights an unusual target on DCs-the α chain of complement receptor 4 (CR4) (CD11c)-for therapeutic interventions in HIV-1 treatment. Targeting CD11c on DCs mediated a potent antiviral immune response via clustering of CR4 and CCR5 and subsequent opening of an antiviral recognition pathway in DCs via MAVS. This novel finding might provide novel tools for specifically boosting endogenous antiviral immunity via CR4, abundantly expressed on multiple DC subsets.