Abstract
Enhancement of human immunodeficiency virus (HIV) infection by complement alone or in conjunction with antibodies was studied experimentally and theoretically. Experimental studies showed that while HIV-positive sera neutralize HIV infection, the addition of fresh complement abrogated neutralization and could even cause enhancement. Enhancement was blocked by anti-complement receptor 2 antibodies, and infection under enhancing conditions could be blocked by soluble CD4. Antibody-dependent complement-mediated enhancement (C'ADE) was dependent on the alternative complement activation pathway, as factor B-deficient serum could enhance only after the addition of factor B. The observed enhancement was also antibody dependent, since the addition of antibodies increased the level of enhancement. Under C'ADE conditions, infection reached a plateau within 5 min and was not caused by activation of cells by factors in the human serum. On the contrary, preincubation of cells with complement decreased the level of enhancement. A theoretical model of HIV infection in vitro which exhibited similar enhancement in an antibody- and complement concentration-dependent way was developed. Model studies indicated that the enhanced infection process could be explained by the fact that virions, because of complement deposition on the surface, bind more efficiently to cells. The model also indicated that the saturation of the enhanced infection process seen after a few minutes could be caused by saturation of the complement receptors. The effect of neutralizing antibodies can thus be overcome by the enhancing effect of complement that facilitates the contact between gp120 and CD4. These studies demonstrate that the main features of the complement-dependent enhancement phenomenon can be understood in terms of a simple mathematical model.