site from long-term survivors of HIV infection.

Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120-CD4-binding site from long-term survivors of HIV infection.

The aim of the study was to identify an HIV epitope suitable for vaccine development. Diverse HIV-1 strains express few structurally constant regions on their surface vulnerable to neutralizing antibodies. The mostly conserved CD4-binding site of gp120 is essential for host cell binding and infection by the virus. Antibodies that recognize the CD4-binding site are rare, and one component of the CD4-binding site, the 421-433 peptide region, expresses B-cell superantigenic character, a property predicted to impair the anti-CD4-binding site adaptive immune response. IgA samples purified from the plasma of patients with HIV infection were analyzed for the ability to bind synthetic mimetics containing the 416-433 gp120 region and full-length gp120. Infection of peripheral blood mononuclear cells by clinical HIV isolates was measured by p24 ELISA. IgA preparations from three patients with subtype B infection for 19-21 years neutralized heterologous, coreceptor CCR5-dependent subtype A, B, C, D, and AE strains with exceptional potency. The IgAs displayed specific binding of a synthetic 416-433 peptide mimetic dependent on recognition of the CD4-binding residues located in this region. Immunoadsorption, affinity chromatography, and mutation procedures indicated that HIV neutralization occurred by IgA recognition of the CD4-binding site. These observations identify the 421-433 peptide region as a vulnerable HIV site to which survivors of infection can produce powerful neutralizing antibodies. This indicates that the human immune system can bypass restrictions on the adaptive B cell response to the CD4-binding site, opening the route to targeting the 421-433 region for attaining control of HIV infection.

Studying the immune response of 3 long-term survivors, who had contracted HIV as children from contaminated blood products 19-21 years previously, revealed a region of HIV that is structurally conserved in genetically diverse HIV strains around the world and is immunogenic, meaning that it stimulates a robust immune response. Purified plasma IgA preparations from each of these 3 patients who were infected with sub-type B neutralized 18 genetically diverse clinical isolates from subtypes A, B, C, D, and AE. This is exciting news because the search for such a conserved epitope, i.e. the part of the virus that is recognized by the immune system and to which an antibody binds, is a holy grail. The site is the 421-433 region of the CD4 binding site of the virus. Interestingly, the autoimmune disease systemic lupus erythematosus produces antibodies to this epitope - and HIV and lupus rarely co-exist.