Analysis of HIV-induced autoantibodies to cryptic epitopes on human CD4.
Antilymphocyte antibodies, including autoantibodies to CD4, have been reported in AIDS patients and are postulated to contribute to T cell depletion and immunologic dysfunction. In this paper, we characterize and localize binding sites of human anti-CD4 autoantibodies from a number of HIV+ patients. Epitope mapping by ELISA and Western blotting, together with cross-competition experiments, showed that common autoepitopes were localized to at least two topographically separate sites on the fourth domain of sCD4. These sites were partially dependent on the carboxyl terminus of the soluble molecule and were not exposed on full length membrane CD4, even under denaturing Western blotting conditions. Peptide screening identified peptides from the fourth and third domains that were recognized by several, but not all, anti-CD4 serum samples. Soluble CD4 affinity-purified antibodies were predominantly IgG1 and were not induced to bind mCD4 after gp120 binding to T cells. Analysis of HIV seroconversion panels showed that the appearance of anti-CD4 antibodies followed HIV seroconversion by 6 to 12 months and paralleled anti-gp120 reactivity. This suggested a correlation between immune reactivity to envelope and anti-CD4 antibody production. Together, the data indicate that human anti-CD4 antibodies recognize cryptic conformational and linear epitopes on a cleaved form of CD4. These findings suggest that HIV may induce abnormal cleavage of full length CD4, thereby exposing immunogenic self epitopes normally hidden from humoral and cellular immune interactions. This model of abnormal processing of self Ag has general implications for autoantigen exposure in other autoimmune disorders.
Callahan
L N
LN
Retrovirology Section, Food and Drug Administration, Bethesda, MD 20892.
Roderiquez
G
G
Mallinson
M
M
Norcross
M A
MA
D000595:Amino Acid Sequence; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology*; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology*; D000939:Epitopes; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011487:Protein Conformation
D001323:Autoantibodies; D015704:CD4 Antigens; D000939:Epitopes; D007074:Immunoglobulin G; D010455:Peptides