Structural Features of Broadly Neutralizing Antibodies and Rational Design of Vaccine

Despite sequence diversity, glycosylation, and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), antibodies that neutralize diverse HIV-1 strains develop in selected HIV-1-infected individuals. The application of single B cell-based approaches has identified many broad and potent human antibodies from infected donors. Structural studies on antibody recognition of HIV Env have revealed that these broadly reactive antibodies target epitopes covering entire exposed and glycosylated surface on the viral spike; several classes of antibodies recognize the viral spike with converged modes. Critical structural features, such as antibody mimicry of cellular receptors, enable effective HIV-1 neutralization. However, other structural and genetic features, such as long CDR H3, fixed length of CDR L3, restricted germline usage, and high rate of somatic hypermutation, may explain the difficulties in eliciting these antibodies by vaccination. Accumulating information on antibody recognition of HIV-1 Env and ontogenesis suggests distinct pathways for generating effective HIV-1 vaccine based on specific antibody ontogeny or specific target site.