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dc.contributor.authorPednekar, L-
dc.contributor.authorPandit, H-
dc.contributor.authorPaudyal, B-
dc.contributor.authorKaur, A-
dc.contributor.authorAl-Mozaini, M-
dc.contributor.authorKouser, L-
dc.contributor.authorGhebrehiwet, B-
dc.contributor.authorMitchell, DA-
dc.contributor.authorMadan, T-
dc.contributor.authorKishore, U-
dc.identifier.citationPednekar, L., Pandit, H., Paudyal, B., Kaur, A., Al-Mozaini, M.A., Kouser, L., Ghebrehiwet, B., Mitchell, D.A., Madan, T. and Kishore, U. (2016) 'Complement Protein C1q Interacts with DC-SIGN via Its Globular Domain and Thus May Interfere with HIV-1 Transmission', Frontiers in Immunology, 7, 600, pp. 1-15. doi: 10.3389/fimmu.2016.00600.en_US
dc.description.abstractDendritic Cells (DCs) are the most potent antigen presenting cells capable of priming naïve T cells. Its C-type lectin receptor, DC-SIGN, regulates a wide range of immune functions. Along with its role in HIV-1 pathogenesis through complement opsonization of the virus, DC-SIGN has recently emerged as an adaptor for complement protein C1q on the surface of immature DCs via a trimeric complex involving gC1qR, a receptor for the globular domain of C1q. Here, we have examined the nature of interaction between C1q and DC-SIGN in terms of domain localization, and implications of C1q-DC-SIGN-gC1qR complex formation on HIV-1 transmission. We first expressed and purified recombinant extracellular domains of DC-SIGN and its homologue SIGN-R as tetramers comprising of the entire extra cellular domain including the α-helical neck region, and monomers comprising of the carbohydrate recognition domain only. Direct binding studies revealed that both DC-SIGN and SIGN-R were able to bind independently to the recombinant globular head modules ghA, ghB and ghC, with ghB being the preferential binder. C1q appeared to interact with DC-SIGN or SIGN-R in a manner similar to IgG. Mutational analysis using single amino acid substitutions within the globular head modules showed that TyrB175 and LysB136 38 were critical for the C1q-DC-SIGN/SIGN-R interaction. Competitive studies revealed that gC1qR and ghB shared overlapping binding sites on DC-SIGN, implying that HIV- 1 transmission by DCs could be modulated due to the interplay of gC1qR-C1q with DC-SIGN. Since C1q, gC1qR and DC-SIGN can individually bind HIV-1, we examined how C1q and gC1qR modulated HIV-1-DC-SIGN interaction in an infection assay. Here, we report, for the first time, that C1q suppressed DC-SIGN-mediated transfer of HIV-1 to activated PBMCs, although the globular head modules did not. The protective effect of C1q was negated by the addition of gC1qR. In fact, gC1qR enhanced DC-SIGN-mediated HIV-1 transfer, suggesting its role in HIV-1 pathogenesis. Our results highlight the consequences of multiple innate immune pattern recognition molecules forming a complex that can modify their functions in a way which may be advantageous for the pathogen.en_US
dc.publisherFrontiers Mediaen_US
dc.rightsCopyright: © 2016 Pednekar, Pandit, Paudyal, Kaur, Al-Mozaini, Kouser, Ghebrehiwet, Mitchell, Madan and Kishore. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.-
dc.titleComplement protein C1q interacts with DC-SIGN via its globular domain, and thus may interfere with HIV-1 transmissionen_US
dc.relation.isPartOfFrontiers in Immunology-
Appears in Collections:Dept of Life Sciences Research Papers

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