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* Medical Research Council Immunochemistry Unit, Department of Biochemistry and
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;
The Hospital for Sick Children Research Institute and University of Toronto, Toronto, Ontario, Canada;
Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, United Kingdom; and
¶ Department of Child Health, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
The identification of surfactant protein A (SP-A) as an important innate immune factor of the lungs, amniotic fluid, and the vaginal tract suggests that it could play an important role during various stages of HIV disease progression and transmission. Therefore, we examined whether SP-A could bind to HIV and also had any effect on viral infectivity. Our data demonstrate that SP-A binds to HIV in a calcium-dependent manner that is inhibitable by mannose and EDTA. Affinity capture of the HIV viral lysate reveals that SP-A targets the envelope glycoprotein of HIV (gp120), which was confirmed by ELISA using recombinant gp120. Digestion of gp120 with endoglycosidase H abrogates the binding of SP-A, indicating that the high mannose structures on gp120 are the target of the collectin. Infectivity studies reveal that SP-A inhibits the infection of CD4+ T cells by two strains of HIV (BaL, IIIB) by >80%. Competition assays with CD4 and mAbs F105 and b12 suggest that SP-A inhibits infectivity by occlusion of the CD4-binding site. Studies with dendritic cells (DCs) demonstrate that SP-A enhances the binding of gp120 to DCs, the uptake of viral particles, and the transfer of virus from DCs to CD4+ T cells by >5-fold at a pH representative of the vaginal tract. Collectively, these results suggest that SP-A acts as a dual modulator of HIV infection by protecting CD4+ T cells from direct infection but enhancing the transfer of infection to CD4+ T cells mediated by DCs.
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 the Medical Research Council (U.K.).
2 Address correspondence and reprint requests to Professor Howard W. Clark, Head, Department of Child Health, MP 803 Southampton General Hospital, Tremona Road, Southampton, United Kingdom SO16 6YD. E-mail address: H.W.Clark{at}soton.ac.uk
3 Abbreviations used in this paper: SP-A, surfactant protein A; SP, surfactant protein; BAL, brocheoalveolar lavage; CD4BS, CD4 binding site; MAb, monoclonal antibody; iMDDC, immature monocyte derived dendritic cell; EndoH, endoglycosidase H; CRD, carbohydrate recognition domain; MBL, mannan-binding lectin; DC-SIGN, DC-specific ICAM-3 grabbing non-integrin; AT-2, aldrithiol-2; TSE, Tris saline EDTA; TMB, tetramethylbenzene; R10, RPMI 1640 plus 10% (v/v) FCS plus 50 U/mL penicillin/streptomycin plus 2 mM L-Glutamine; CHO, Chinese hamster ovary; CVN, cyanovirin; GlcNAc, N-acetyl glucosamine.
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