title: Efficient capture of antibody neutralized HIV-1 by cells expressing DC-SIGN and transfer to CD4+ T lymphocytes.
abstract: Infection of CD4+ T lymphocytes is enhanced by the capture and subsequent transfer of HIV-1 by dendritic cells (DCs) via the interaction with C-type lectins such as the DC-specific ICAM-grabbing nonintegrin (DC-SIGN). Numerous HIV-1 envelope-directed neutralizing Abs have been shown to successfully block the infection of CD4(+) T lymphocytes. In this study, we find that HIV-1-neutralized with the mAb 2F5 is more efficiently captured by immature monocyte-derived DCs (iMDDCs) and DC-SIGN-expressing Raji cells (Raji-DC-SIGN). Furthermore, a 2F5-neutralized virus captured by these cells was able to subsequently infect CD4+ T lymphocytes upon the release of HIV-1 from iMDDCs, thereby enhancing infection. We show that upon transfer via DC-SIGN-expressing cells, HIV-1 is released from immune-complexes with the Abs 2F5 and 4E10 (gp41-directed) and 2G12, 4.8D, and 1.7b (gp120-directed). The nonneutralizing V3-21 (V3 region of the gp120-directed) Ab enhanced HIV-1 infection upon capture and transfer via Raji-DC-SIGN cells, whereas no infection was observed with the neutralizing b12 Ab (gp120-directed), indicating that different Abs have variant effects on inhibiting HIV-1 transfer to CD4+ T lymphocytes. The increased capture of the 2F5-neutralized virus by iMDDCs was negated upon blocking the Fc receptors. Blocking DC-SIGN on iMDDCs resulted in a 70-75% inhibition of HIV-1 capture at 37 degrees C, whereas at 4 degrees C a full block was observed, showing that the observed transfer is mediated via DC-SIGN. Taken together, we propose that DC-SIGN-mediated capture of neutralized HIV-1 by iMDDCs has the potential to induce immune evasion from the neutralization effects of HIV-1 Abs, with implications for HIV-1 pathogenesis and vaccine development.
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Center of Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Meibergdreef 15, Amsterdam, The Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: van Montfort
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Nabatov
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
authors.forename: Georgios
authors.initials: G
authors.lastname: Pollakis
authors.forename: William A
authors.initials: WA
authors.lastname: Paxton
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D015870:Gene Expression; D015483:HIV Antibodies / Q000276:immunology* / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000635:transmission; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000276:immunology* / Q000821:virology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011961:Receptors, Fc / Q000037:antagonists & inhibitors / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin