Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01–12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30–38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development. A longitudinal study of an individual patient developing neutralizing antibodies against HIV-1 (targeting the V1V2 region of gp120) reveals how such neutralizing antibodies develop and evolve over time, providing important insights relevant to vaccine development. A better understanding of how HIV-1-neutralizing antibodies are generated could be a useful contribution to the design of improved AIDS vaccines. John Mascola and colleagues have now elucidated the immunological pathway of an important category of HIV-1-neutralizing antibody — those that target the variable V1V2 region of the viral envelope. These antibodies are more frequently elicited than CD4-binding site antibodies in the early stages of HIV infection and feature modest affinity maturation, a process that favours mutations in antibody variable domains that enhance antigen binding.

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies