Non-covalent complexes of HIV gp120 with CD4 and/or mAbs enhance activation of gp120-specific T clones and provide intermolecular help for anti-CD4 antibody production

The ‘dangerous liaison’ between CD4 and gp120 thatoffers the first entry opportunity to HIV may also provoke perturbationsof the immune control of the host with far-reaching immunopathologicalconsequences. We wondered whether a mechanism of intermolecularhelp (T help across the gap of a non-covalent bond, in contrastto the interamolecular help of carrier to hapten) could breakself-tolerance and be the cause of the frequent anti-CD4 autoantibodiesfound in AIDS patients. To determine whether this hypothesisdeserves further testing, we designed a series of in vitro andin vivo experiments of increasing complexity, focused on thepresentation of gp120 to specific T cells by antigen presentingcells (APC) exposed to the envelope protein in the form of non-covalentcomplexes. Bi-molecular complexes were constructed by allowinggp120 or gp160 to bind specific human mAbs. Tri-molecular complexeswere constructed by introducing CD4 as an intermediate ligandbetween gp120 and mouse mAbs specific for CD4. In all casesthe use of complexes did enhance the immunogenic capacity ofsubstimulatory doses of gp120 or gp160 by facilitating uptakeby APC via Fc receptor and consequent presentation to specifichuman T cell clones. Finally, help for the production in vivoof anti-CD4 antibodies was obtained from T lymphocytes specificfor gp120 when CD4-primed memory B cells were pulsed with CD4complexed with gp120, thus demonstrating in the mouse the entirecycle of intermolecular help via non-covalent interaction, andsetting the stage for future experiments on self-tolerance breakagein a human molecular context.