Deletions in variable region 1 of the HIV envelope accelerate V3-glycan bNAb induction in SHIV-infected rhesus macaques.

Elicitation of broadly neutralizing antibodies (bNAbs) is a major goal of HIV-1 vaccine research. V3-glycan bNAbs were previously identified in a person living with HIV-1, CH848, and in two of six rhesus macaques (RMs) infected with a simian-HIV (SHIV) expressing the CH848 transmitted/founder envelope (Env) glycoprotein. In all cases, neutralization breadth developed after years of infection and only after the variable region 1 (V1) of Env had shortened in response to neutralizing antibodies. These observations suggested that V3-glycan bNAb elicitation might be accelerated if RMs were infected with SHIVs bearing CH848 Envs with truncated V1 loops. To test this hypothesis, we analyzed NAb responses in 10 RMs infected with SHIV.CH848 variants containing V1 deletions that mimicked those observed in natural infection. In three RMs, potent V3-glycan bNAbs developed within 1 y of infection, nearly three times faster than in wildtype CH848 infection. Longitudinal sequencing of B cell immunoglobulin genes revealed a single bNAb lineage in each RM that was primed as early as 8 to 12 wk postinfection and that largely recapitulated plasma breadth. A meta-analysis of the frequency of V3-glycan bNAb induction in RMs infected by SHIVs expressing CH848-derived Envs vs. 15 other primary HIV-1 Envs demonstrated a substantial enhancement in the CH848 group (5 of 16 vs. 2 of 109; P = 0.0003). We conclude that CH848 Envs have a propensity for inducing V3-glycan bNAbs and that truncations in their V1 loops accelerate precursor priming, findings that may guide HIV-1 vaccine design and inform current human vaccine trials.