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Bifunctional CD4-DC-SIGN fusion proteins demonstrate enhanced avidity to gp120 and inhibit HIV-1 infection and dissemination.

Du, T; Hu, K; Yang, J; Jin, J; Li, C; Stieh, D; Griffin, GE; Shattock, RJ; Hu, Q (2012) Bifunctional CD4-DC-SIGN fusion proteins demonstrate enhanced avidity to gp120 and inhibit HIV-1 infection and dissemination. Antimicrob Agents Chemother, 56 (9). pp. 4640-4649. ISSN 1098-6596 https://doi.org/10.1128/AAC.00623-12
SGUL Authors: Griffin, George Edward Hu, Qinxue

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Abstract

Early stages of mucosal infection are potential targets for HIV-1 prevention. CD4 is the primary receptor in HIV-1 infection whereas DC-SIGN likely plays an important role in HIV-1 dissemination, particularly during sexual transmission. To test the hypothesis that an inhibitor simultaneously targeting both CD4 and DC-SIGN binding sites on gp120 may provide a potent anti-HIV strategy, we designed constructs by fusing the extracellular CD4 and DC-SIGN domains together with varied arrangements of the lengths of CD4, DC-SIGN and the linker. We expressed, purified and characterized a series of soluble CD4-linker–DC-SIGN (CLD) fusion proteins. Several CLDs, composed of a longer linker and an extra neck domain of DC-SIGN, had enhanced affinity for gp120 as evidenced by molecular-interaction analysis. Furthermore, such CLDs exhibited significantly enhanced neutralization activity against both laboratory-adapted and primary HIV-1 isolates. Moreover, CLDs efficiently inhibited HIV-1 infection in trans via a DC-SIGN-expressing cell line and primary human dendritic cells. This was further strengthened by the results from the human cervical explant model, showing that CLDs potently prevented both localized and disseminated infections. This is the first time that soluble DC-SIGN-based bifunctional proteins have demonstrated anti-HIV potency. Our study provides proof of the concept that targeting both CD4 and DC-SIGN binding sites on gp120 represents a novel antiviral strategy. Given that DC-SIGN binding to gp120 increases exposure of the CD4 binding site and that the soluble forms of CD4 and DC-SIGN occur in vivo, further improvement of CLDs may render them potentially useful in prophylaxis or therapeutics.

Item Type: Article
Additional Information: Copyright © 2012, American Society for Microbiology. All Rights Reserved.
Keywords: Binding Sites, CD4 Antigens, Cell Adhesion Molecules, Cell Line, Dendritic Cells, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Kinetics, Lectins, C-Type, Plasmids, Primary Cell Culture, Receptors, Cell Surface, Receptors, Virus, Recombinant Fusion Proteins, Solubility, Transfection, Dendritic Cells, Cell Line, Humans, HIV-1, HIV Infections, Cell Adhesion Molecules, Lectins, C-Type, Receptors, Cell Surface, Receptors, Virus, Antigens, CD4, Recombinant Fusion Proteins, HIV Envelope Protein gp120, Transfection, Binding Sites, Kinetics, Plasmids, Solubility, Primary Cell Culture, Science & Technology, Life Sciences & Biomedicine, Microbiology, Pharmacology & Pharmacy, MICROBIOLOGY, PHARMACOLOGY & PHARMACY, HUMAN-IMMUNODEFICIENCY-VIRUS, SEDIMENTATION-VELOCITY ULTRACENTRIFUGATION, HUMAN CERVICAL TISSUE, CD4(+) T-LYMPHOCYTES, DC-SIGN, DENDRITIC CELLS, SOLUBLE CD4, BINDING-SITE, TYPE-1 ENVELOPE, TRANS-INFECTION, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology And Pharmaceutical Sciences, Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Antimicrob Agents Chemother
ISSN: 1098-6596
Language: eng
Dates:
DateEvent
17 August 2012Published
11 June 2012Published Online
6 June 2012Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
2010CB530100Ministry of Science and Technology of the People's Republic of Chinahttp://dx.doi.org/10.13039/501100002855
2012ZX10001006-02Ministry of Science and Technology of the People's Republic of Chinahttp://dx.doi.org/10.13039/501100002855
30872357National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
30770100National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
KSCX2-YW-R- 144Chinese Academy of Scienceshttp://dx.doi.org/10.13039/501100002367
PubMed ID: 22687513
Web of Science ID: WOS:000307908600009
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107644
Publisher's version: https://doi.org/10.1128/AAC.00623-12

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