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Efficient Capture of Antibody Neutralized HIV-1 by Cells Expressing DC-SIGN and Transfer to CD4⁺ T Lymphocytes^1,2

Thijs van Montfort^*, Alexey A. Nabatov^3,*,, Teunis B. H. Geijtenbeek, Georgios Pollakis^* and William A. Paxton^4,*

^* Laboratory of Experimental Virology, Department of Medical Microbiology, Center of Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, The Netherlands; and Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center Amsterdam, The Netherlands

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°C, whereas at 4°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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the European Union (QLK2-CT-1999-01321 and QLK2-CT-2001-01316 "Eurovac-I and -II") and the Royal Dutch Academy for Arts and Sciences (to W.A.P.).

² T.v.M. designed and performed the experiments, A.A.N. designed experiments and supplied dendritic cells, T.G. and G.P. contributed vital reagents, and W.A.P. supervised the study and participated in writing of the paper.

³ Current address: Department of Molecular Cell Biology and Immunology, Vrije Univeriteit Medical Center, Amsterdam, The Netherlands.

⁴ Address correspondence and reprint requests to Dr. William A. Paxton, Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, Amsterdam, The Netherlands. E-mail address: w.a.paxton{at}amc.uva.nl

⁵ Abbreviations used in this paper: DC, dendritic cell; DC-SIGN, DC-specific ICAM-grabbing nonintegrin; iDC, immature DC; iMDDC, immature monocyte-derived DC; IC, immune-complex; siRNA, small interfering RNA; TCID₅₀, 50% tissue culture infectious dose.

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