TY - JOUR
T1 - Complement Potentiates Immune Sensing of HIV-1 and Early Type I Interferon Responses
AU - Posch, Wilfried
AU - Bermejo-Jambrina, Marta
AU - Steger, Marion
AU - Witting, Christina
AU - Diem, Gabriel
AU - Hörtnagl, Paul
AU - Hackl, Hubert
AU - Lass-Flörl, Cornelia
AU - Huber, Lukas A.
AU - Geijtenbeek, Teunis B. H.
AU - Wilflingseder, Doris
N1 - Funding Information: The study was funded by the Austrian National Bank (OeNB Jubiläumsfonds, number 17614 to W.P.), the Austrian Science Fund (FWF; number P33510 to D.W.), and graduate programs MCBO (W11 to D.W.) and CBD (Cellular Basis of Diseases) (FWF DOC 82 to D.W.). Funding Information: We thank our technician Karolin Thurnes and Paula Jauregui-Onieva for their valuable help and support regarding this work. We thank Oliver Keppler, Nathaniel Landau, and Thomas J. Hope for providing reagents and virus plasmids. We also thank Polymun Scientific, Klosterneuburg, Austria, who provided all reagents for p24 ELISA. The reagents ARP118 (HIV-BaL) and ARP177.8 (HIV-92UG037) were obtained from the Centre for AIDS Reagents, NIBSC HPA UK, supported by the EC FP6/7 Europrise Network of Excellence, and NGIN consortia and the Bill and Melinda Gates GHRC-CAVD Project and were donated by S. Gartner, M. Popovic, R. Gallo (courtesy of the NIH AIDS Research and Reference Reagent Program [BaL]), and the WHO UN AIDS Network for HIV-isolation and characterization [92UG037]. Funding Information: We thank our technician Karolin Thurnes and Paula Jauregui-Onieva for their valuable help and support regarding this work. We thank Oliver Keppler, Nathaniel Landau, and Thomas J. Hope for providing reagents and virus plasmids. We also thank Polymun Scientific, Klosterneuburg, Austria, who provided all reagents for p24 ELISA. The reagents ARP118 (HIV-BaL) and ARP177.8 (HIV-92UG037) were obtained from the Centre for AIDS Reagents, NIBSC HPA UK, supported by the EC FP6/7 Europrise Network of Excellence, and NGIN consortia and the Bill and Melinda Gates GHRC-CAVD Project and were donated by S. Gartner, M. Popovic, R. Gallo (courtesy of the NIH AIDS Research and Reference Reagent Program [BaL]), and the WHO UN AIDS Network for HIV-isolation and characterization [92UG037]. The study was funded by the Austrian National Bank (OeNB Jubil?umsfonds, number 17614 to W.P.), the Austrian Science Fund (FWF; number P33510 to D.W.), and graduate programs MCBO (W11 to D.W.) and CBD (Cellular Basis of Diseases) (FWF DOC 82 to D.W.). Conceptualization of the study, D.W. and W.P.; Formal Analysis, H.H.; Experiments and Investigation, W.P., M.B.-J., M.S., C.W., G.D., P.H., L.A.H., and D.W.; Data Curation, H.H.; Writing ? Original Draft, D.W. and W.P.; Writing ? Review and Editing, D.W., T.B.H.G., C.L.-F., L.A.H., and W.P.; Funding Acquisition, W.P. and D.W.; Supervision, C.L.-F. and T.B.H.G.; Project Administration, D.W. and W.P. We declare no conflict of interest. Publisher Copyright: Copyright © 2021 Posch et al.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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-kB 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 a 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.
AB - 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-kB 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 a 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.
KW - Antiviral immunity
KW - CR4
KW - Complement
KW - Complement receptors
KW - Cytosolic sensor
KW - Dendritic cell
KW - Dendritic cells
KW - HIV-1
KW - Human immunodeficiency virus
KW - Type I IFN
UR - http://www.scopus.com/inward/record.url?scp=85121015222&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/mBio.02408-21
DO - https://doi.org/10.1128/mBio.02408-21
M3 - Article
C2 - 34634939
SN - 2161-2129
VL - 12
SP - e0240821
JO - MBio
JF - MBio
IS - 5
M1 - e02408-21
ER -