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

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. IMPORTANCE 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.

Infection and transmission of SARS-CoV-2 depend on heparan sulfate proteoglycans.

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.

Role of Complement Receptors (CRs) on DCs in Anti-HIV-1 Immunity.

Upon entry of human immunodeficiency virus 1 (HIV-1) into the host, innate immune mechanisms are acting as a first line of defense, that considerably also modify adaptive immunity by the provision of specific signals. Innate and adaptive immune responses are intimately linked and dendritic cells (DCs) together with complement (C) play an important role in regulation of adaptive immunity. Initially, the role of complement was considered to primarily support - or COMPLEMENT - cytolytic actions of antibodies or antibody-complexed antigens (immune complexes, ICs) or directly kill the pathogens by complement-mediated lysis. Recently, the role of complement was revised and found to significantly augmenting and modulating adaptive immunity, in particular against viruses. Complement and DCs are therefore predestined to open novel avenues for antiviral research and potential therapeutic interventions. Recent studies on interactions of complement-opsonized HIV-1 with DCs demonstrated a high potential of such primed DCs to initiate efficient antiviral and cytotoxic anti-HIV-1 immunity and complement-coated viral particles shift DCs functions via CR3 and CR4 in an antithetic manner. This review will focus on our current knowledge of CR3 and CR4 actions on DCs during HIV-1 binding and the outcome of infection influenced by entry and signaling pathways.