van Montfort Thijs, Nabatov Alexey A, Geijtenbeek Teunis B H, Pollakis Georgios, Paxton William A
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.
J Immunol. 2007 Mar 1;178(5):3177-85. doi: 10.4049/jimmunol.178.5.3177.
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.
树突状细胞（DCs）通过与C型凝集素（如DC特异性细胞间黏附分子抓取非整合素，即DC-SIGN）相互作用捕获并随后转移HIV-1，从而增强CD4+ T淋巴细胞的感染。许多针对HIV-1包膜的中和抗体已被证明能成功阻断CD4(+) T淋巴细胞的感染。在本研究中，我们发现用单克隆抗体2F5中和的HIV-1能更有效地被未成熟单核细胞衍生的DCs（iMDDCs）和表达DC-SIGN的Raji细胞（Raji-DC-SIGN）捕获。此外，这些细胞捕获的经2F5中和的病毒在从iMDDCs释放HIV-1后能够随后感染CD4+ T淋巴细胞，从而增强感染。我们表明，通过表达DC-SIGN的细胞进行转移时，HIV-1会从与抗体2F5、4E10（针对gp41）以及2G12、4.8D和1.7b（针对gp120）形成的免疫复合物中释放出来。非中和性的V3-21（针对gp120的V3区）抗体在通过Raji-DC-SIGN细胞捕获和转移后增强了HIV-1感染，而针对gp120的中和性b12抗体则未观察到感染，这表明不同抗体对抑制HIV-1转移至CD4+ T淋巴细胞具有不同作用。阻断Fc受体后，iMDDCs对2F5中和病毒的捕获增加被消除。在37℃下阻断iMDDCs上的DC-SIGN导致HIV-1捕获受到70 - 75%的抑制，而在4℃下则观察到完全阻断，表明所观察到的转移是通过DC-SIGN介导的。综上所述，我们提出iMDDCs通过DC-SIGN介导捕获中和的HIV-1有可能诱导对HIV-1抗体中和作用的免疫逃逸，这对HIV-1发病机制和疫苗开发具有重要意义。
