Differential Modulation of Human Lactoferrin Activity against Both R5 and X4-HIV-1 Adsorption on Epithelial Cells and Dendritic Cells by Natural Antibodies

Abstract

Human lactoferrin (Lf) is an iron binding glycoprotein that is present in several mucosal secretions. Many biological functions have been ascribed to Lf. In the present study, we showed that Lf limited specifically adsorption of R5- and X4-HIV-1-free particles on endometrial epithelial HEC-1A cells, by inhibiting virus adsorption on heparan-sulfated proteoglycans. But, Lf did not interfere with both R5 and X4-HIV transcytosis. We showed also the efficacy of Lf in preventing R5 and X4-HIV capture by dendritic cells. Conversely, we demonstrated that Lf-reacting natural Abs (NAbs) present within i.v. Ig-enhanced HIV attachment on dendritic cells by forming HIV-Lf-NAbs. HIV particles were able to directly interact with Lf following its interaction with NAbs. We also found Lf-reacting natural Abs within cervicovaginal secretions, suggesting the existence of Lf-NAbs complexes in women genital tract in vivo. In conclusion, this study highlights Lf as a potent microbicides and reports new function for NAbs within the genital compartment that may compartment that may abolish the inhibitory activity of microbicide compounds. Thus, we proposed a model in which Lf would appear as a double-edged sword that could have beneficial or detrimental effects depending on both cellular and molecular environments. This study highlights the use of Lf derivates as microbicide candidates to limit such interferences.

Lactoferrin as a Natural Immune Modulator

“…The ability of lactoferrin to promote antigen specific DTH responses and BCG specific T-cell activation indicates a role in the initiation of T-cell activation, perhaps through modulation of dendritic cell function. Similar to macrophages, dendritic cells possess lactoferrin receptors as both bovine and human lactoferrin can bind to the surface of peripheral blood derived dendritic cells [102,133]. …”

“…Both bovine and human lactoferrin bind to the surface of THP-1 cells, a human monocytic cell line. Binding can be reduced by inhibiting sulphation on the cell surface [115, 133, 195]. Both human and bovine lactoferrin bind purified heparin sulfate chains, and to a lesser extent, chondroitin sulfate chains.…”

Differential activity of candidate microbicides against early steps of HIV-1 infection upon complement virus opsonization

“…Peripheral blood mononuclear cells (PBMC) were isolated from buffy coats of healthy adult donors by Ficoll density gradient centrifugation on Medium for Separation of Lymphocytes (MSL, Eurobio, Les Ulis, France), as previously described [14]. The percentage of monocytes was determined by flow cytometry using forward scatter and side scatter properties (FSC/SSC).…”

“…The gp120-interacting sulfated polyvinyl alcohol (PVAS) which inhibits the virus entry, (molecular weight, 20,000 Da) was synthesized in the form of its sodium salts by the sulfation of PVA (polyvinyl alcohol) with chlorosulfonic acid in pyridine-dimethylformamide solution [17]. Human lactoferrin (Lf) [18] which limits the HIV-1 attachment on dendritic cells by inhibiting virus attachment on heparan sulfate proteoglycans [14] and mannan were obtained from Sigma-Aldrich (Saint-Louis, MO). CADA (cyclotriazadisulfonamide) [19] which inhibits the HIV entry by CD4 receptor down-modulating, was supplied by T.W.…”

“…After 4 washes to remove unattached virus, cells were lysed by adding PBS 1% Triton X-100 for 45 min at 37°C, and the concentration of HIV-1 p24 antigen was measured [14]. Polyclonal purified antibodies to gp160 and mannan were used as positive controls.…”