We have been studying the magnitude, breadth, kinetics and epitope specificity of the neutralizing antibody (nAb) response in early and chronic HIV-1 infection. The earliest nAb response was highly specific for the early autologous virus but within 1–2 years of infection, low titers of broadly neutralizing activity were detected in a subset of subjects. High titers of broadly neutralizing activity were detected in ∼15% of chronically infected individuals (outstanding neutralizers). The earliest autologous nAb response in two HIV-1 subtype B-infected individuals targeted a novel 332-glycan-dependent epitope in a 4-stranded antiparallel sheet immediately below the base of the V3-loop, near the coreceptor binding domain of gp120. This same glycan was required for the heterologous neutralizing activity of serum samples from 3/9 of the most outstanding neutralizers in our chronic infection cohort. Additional broadly neutralizing epitopes were targeted by these 9 subjects, including MPER (3 subjects), PG9/16-like (2 subjects) and CD4bs (1 subject). Some broadly neutralizing activity could not be mapped with current technologies. Serum from a subset of outstanding neutralizers targeted multiple conserved nAb epitopes, including one subject who made both PG9-like and VRC01-like nAbs, providing proof-of-concept for polyvalent vaccine immunogens. Serum samples from 6 outstanding neutralizers examined were capable of neutralizing multiple variants in the contemporaneous viral quasispecies, suggesting that escape from broadly nAbs is limited by fitness constraints. This collective information is useful for identifying new mAbs, delineating the ontogeny of broadly nAb responses and designing novel vaccine immunogens.
© 2012 Lippincott Williams & Wilkins, Inc.