Syndecan-Fc hybrid molecule as a potent in vitro microbicidal anti-HIV-1 agent.
In the absence of a vaccine, there is an urgent need for the development of safe and effective topical microbicides to prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In this study, we proposed to develop a novel class of microbicides using syndecan as the antiviral agent. Specifically, we generated a soluble syndecan-Fc hybrid molecule by fusing the ectodomain of syndecan-1 to the Fc domain of a human IgG. We then tested the syndecan-Fc hybrid molecule for various in vitro microbicidal anti-HIV-1 properties. Remarkably, the syndecan-Fc hybrid molecule possesses multiple attractive microbicidal properties: (i) it blocks HIV-1 infection of primary targets including T cells, macrophages, and dendritic cells (DC); (ii) it exhibits a broad range of antiviral activity against primary HIV-1 isolates, multidrug resistant HIV-1 isolates, HIV-2, and simian immunodeficiency virus (SIV); (iii) it prevents transmigration of HIV-1 through human primary genital epithelial cells; (iv) it prevents HIV-1 transfer from dendritic cells to CD4(+) T cells; (v) it is potent when added 2 h prior to addition of HIV-1 to target cells; (vi) it is potent at a low pH; (vii) it blocks HIV-1 infectivity when diluted in genital fluids; and (viii) it prevents herpes simplex virus infection. The heparan sulfate chains of the syndecan-Fc hybrid molecule are absolutely required for HIV-1 neutralization. Several lines of evidence suggest that the highly conserved Arg298 in the V3 region of gp120 serves as the locus for the syndecan-Fc hybrid molecule neutralization. In conclusion, this study suggests that the syndecan-Fc hybrid molecule represents the prototype of a new generation of microbicidal agents that may have promise for HIV-1 prevention.
Bobardt
Michael D
MD
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Chatterji
Udayan
U
Schaffer
Lana
L
de Witte
Lot
L
Gallay
Philippe A
PA
D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000821:virology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000821:virology; D016662:Virus Integration / Q000187:drug effects
D019380:Anti-HIV Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D053668:Syndecan-1