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Survivors of HIV infection produce potent, broadly neutralizing IgAs directed to the superantigenic region of the gp120 CD4 binding site
Presented by Stephanie Planque, United States.
S. Planque1, M. Salas2, M.E. Escobar3, M.-K. Morris2, B. Jena1, Y. Mitsuda1, M. Sienczyk1, Y. Nishiyama1, A. Kumar4, F. Gao4, D.C. Montefiori5, C.V. Hanson2, S. Paul1
1University of Texas-Houston Medical School, Pathology, Houston, United States, 2California Department of Public Health, Viral and Rickettsial Disease Laboratory, Richmond, United States, 3University of Texas–Houston Medical School, Pediatrics, Houston, United States, 4Duke University, Medicine, North Carolina, United States, 5Duke University, Surgery, North Carolina, United States
Background: HIV disease progression can occur slowly. Preimmune antibodies (Abs) recognize the conserved 416-433 residues in the B cell superantigenic determinant of gp120, which also contains essential amino acids necessary for HIV binding to CD4 receptors. We previously identified IgAs in uninfected humans that recognize the 416-433 epitope, catalyze the degradation of gp120 and neutralize HIV with modest potency. Here, we report the anti-HIV properties of IgAs from long-term survivors of HIV infection.
Methods: Neutralization of clinical HIV isolates by purified plasma IgA was measured by p24 assay using peripheral blood mononuclear cells. Binding of electrophilic analogs of gp120 V3 peptide 306-328 (E-306-328) and CD4 binding peptide 416-433 (E-416-433) was determined by ELISA. gp120 hydrolysis was monitored electrophoretically.
Results: Sub-µg to µg/ml purified IgAs from 3 hemophilia A subjects with 17-21 years clade B infection and little or no anti-retroviral therapy (S17-21 survivors) neutralized all 18 heterologous, CCR5-dependent strains tested (clade A, B, C, D and AE). Neutralization potencies and breadths were favorable compared to monoclonal IgG b12; IgAs from uninfected subjects; and IgAs from infected subjects who succumbed to AIDS or survived without AIDS for 5 years. CXCR4-dependent strains were neutralized poorly. Pseudovirions of certain neutralizable clinical isolates were not neutralized. S17-21 IgAs hydrolyzed recombinant gp120 detectably and displayed binding of E-gp120, V3 E-306-328 and the superantigenic E-416-433 peptide. Depletion of the E-416-433 binding IgA subset resulted in loss of HIV neutralizing activity.
Conclusions: Potent and broad HIV neutralization suggest that the IgAs slow the progression of HIV disease. The superantigenic character of the 416-433 epitope may explain the unusual adaptive IgA response occurring very late in infection. The IgA properties identify the 416-433 epitope as a suitable target for vaccine-induced prophylaxis against the virus. Supported by NIH grants AI058865, AI067020, AI071951, AI062455.