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* Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY 12208;
Department of Medicine, Children’s Hospital and Harvard Medical School, Boston, MA 02115;
Division of Infectious Diseases, Colorado Center for AIDS Research, University of Colorado and Health Sciences Center, Department of Veterans Affairs Eastern Colorado Health Care System, Denver, CO 80262;
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; and
¶ Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Both IgG and secretory IgA Abs in mucosal secretions have been implicated in blocking the earliest events in HIV-1 transit across epithelial barriers, although the mechanisms by which this occurs remain largely unknown. In this study, we report the production and characterization of a human rIgA2 mAb that carries the V regions of IgG1 b12, a potent and broadly neutralizing anti-gp120 Ab which has been shown to protect macaques against vaginal simian/HIV challenge. Monomeric, dimeric, polymeric, and secretory IgA2 derivatives of b12 reacted with gp120 and neutralized CCR5- and CXCR4-tropic strains of HIV-1 in vitro. With respect to the protective effects of these Abs at mucosal surfaces, we demonstrated that IgG1 b12 and IgA2 b12 inhibited the transfer of cell-free HIV-1 from ME-180 cells, a human cervical epithelial cell line, as well as Caco-2 cells, a human colonic epithelial cell line, to human PBMCs. Inhibition of viral transfer was due to the ability of b12 to block both viral attachment to and uptake by epithelial cells. These data demonstrate that IgG and IgA MAbs directed against a highly conserved epitope on gp120 can interfere with the earliest steps in HIV-1 transmission across mucosal surfaces, and reveal a possible mechanism by which b12 protects the vaginal mucosal against viral challenge in vivo.
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 National Institutes of Health Grants AI33292 and AI55332 (to D.R.B.), Grants HD-41361, AI-48796, P30 AI-054907 (to E.N.J.), and Grant AI034757 (to M.R.N.). E.N.J. received additional support from the Veterans Affairs Research Service and the Colorado Center for AIDS Research. N.J.M. was supported by Mentored Research Scientist Award DK059295.
2 Address correspondence and reprint requests to Dr. Nicholas J. Mantis, Division of Infectious Diseases, Wadsworth Center, 120 New Scotland Avenue, Albany, NY 12208. E-mail address: nmantis{at}wadsworth.org
3 J.P. and A.J.H. contributed equally to this work.
4 Current address: Department of Molecular Microbiology, School of Medicine, Washington University, St. Louis, MO 63110.
5 Abbreviations used in this paper: SHIV, simian/HIV; SIgA, secretory IgA; SC, secretory component; GS, glutamine synthetase; GMEM, glutamine-free MEM; AI, affinity index; TCID50, 50% tissue culture-infective dose; MSX, methionine sulfoximine.
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