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 that offers the first entry opportunity to HIV may also provoke perturbations of the immune control of the host with far-reaching immunopathological consequences. We wondered whether a mechanism of intermolecular help (T help across the gap of a non-covalent bond, in contrast to the intramolecular help of carrier to hapten) could break self-tolerance and be the cause of the frequent anti-CD4 autoantibodies found in AIDS patients. To determine whether this hypothesis deserves further testing, we designed a series of in vitro and in vivo experiments of increasing complexity, focused on the presentation of gp120 to specific T cells by antigen presenting cells (APC) exposed to the envelope protein in the form of non-covalent complexes. Bi-molecular complexes were constructed by allowing gp120 or gp160 to bind specific human mAbs. Tri-molecular complexes were constructed by introducing CD4 as an intermediate ligand between gp120 and mouse mAbs specific for CD4. In all cases the use of complexes did enhance the immunogenic capacity of substimulatory doses of gp120 or gp160 by facilitating uptake by APC via Fc receptor and consequent presentation to specific human T cell clones. Finally, help for the production in vivo of anti-CD4 antibodies was obtained from T lymphocytes specific for gp120 when CD4-primed memory B cells were pulsed with CD4 complexed with gp120, thus demonstrating in the mouse the entire cycle of intermolecular help via non-covalent interaction, and setting the stage for future experiments on self-tolerance breakage in a human molecular context.
Manca
F
F
Department of Immunology, University of Genoa, San Martino Hospital, Italy.
Seravalli
E
E
Valle
M T
MT
Fenoglio
D
D
Kunkl
A
A
Li Pira
G
G
Zolla-Pazner
S
S
Celada
F
F
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D005260:Female; D015483:HIV Antibodies / Q000096:biosynthesis* / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D016056:Immunodominant Epitopes