Mannose residues in HIV-1 aggregation and its dispersion by mucin: Implications for neutralization

HIV-1 is covered by mannose sugars that restrict antibody access to vital antigenic regions on the virus envelop protein. Adhesions between mannose sugars were reported to mediate a self-aggregation of the virus, which could be dispersed by filtration shear or by porcine gastric mucin II (PGM-II). We investigated the implications of HIV-1 aggregation for its infectivity and neutralization, the pH and shear conditions it was likely to occur at, and the mechanism by which commercial PGM-II dispersed the aggregates. Aggregated HIV-1 was several-fold more infective than dispersed virions, but it was equivalently neutralized by antibodies, mannose lectins, mucin, and mannose cleavage. The aggregated state occurred between pH 5 and pH 7.4 and at the lower shear rates where it damped the frictional resistance of the solution nearly 10-fold. We examined the connection of interactions, such as mucin→virus→antibodies→protein A/G, that would allow protein A/G-coated magnetic beads to draw out mucin from solution. Both virus and mucin were pulled out by antibodies against either, confirming close associations between the two. Lectin access to mucin sugars increased, but that to virus sugars decreased in the mucin-virus entities. Mucin appears to bind HIV-1 at the gp120 envelop protein but was displaced by anti-gp120 antibodies. The fragment crystallizable (Fc) of anti-muc antibodies were found interacting with mucin but were displaced by virions competing for that mucin site. Removal or blocking of the mannose N-glycans on mucin disrupted the virus→mucin and the observed Fc→mucin connection. The study highlights a nuanced role for mannose-mannose self-adhesion in virus transmission, serving not only to aggregate the virus into a more infective form, but also providing an avenue for neutralizing the virus by mucin and entities that compete for the virus-virus interaction sites.