Abstract An effective human immunodeficiency virus type I (HIV-1) vaccine that robustly elicits broadly neutralizing antibodies (bnAbs) against HIV-1 envelope glycoproteins (Envs) to block viral entry is still not available. Thus, identifying triggers for elicitation of different types of anti-HIV-1 Env antibodies by vaccination could provide further guidance for immunogen design and vaccine development. Here, we studied the immune response to HIV-1 Env immunogens in rabbits. We show that sequential immunizations with conformation-specific Env immunogens can elicit low titer but broad neutralization responses against heterologous, neutralization-resistant (tier 2/3) transmitted/founder (T/F) HIV-1 strains. More importantly, an mRNA vaccine candidate that could mediate the presentation of a cytoplasmic tail-deleted (ΔCT) HIV-1AD8 Env immunogen on virus-like particles significantly increased the neutralization response. This strategy shifted the type of elicited antibodies, decreasing the level of binding to soluble Envs while significantly increasing their overall viral neutralization activity. The breadth and potency of neutralizing response against heterologous, T/F HIV-1 strains significantly increased in a subset of rabbits. Efficient neutralization activity was associated with high cellular immune responses specific to HIV-1 Envs. These results help to understand the immune response to different immunization schemes and will allow developing new approaches to selectively manipulate the type of humoral immune response by specific vaccination.
