Apex-guided HIV vaccination: liposome-displayed Env trimers elicit PG9-like cross-neutralizing antibodies

Abstract

In a recent Nature study, Guenaga et al. demonstrated that sequential immunization with heterologous NFL-stabilized HIV envelope (Env) trimers displayed on liposomes elicited PG9-like apex-directed cross-neutralizing serum IgG responses in all six immunized rhesus macaques, with neutralization breadth reaching up to 70% across a diverse virus panel. 1 This work provides a structural and immunological proof-of-concept that rational multivalent Env trimer design can guide B-cell maturation toward broadly neutralizing antibodies targeting the glycan-shielded HIV Env apex. An effective prophylactic HIV vaccine remains elusive because HIV combines rapid Env sequence diversi fi cation with dense host-derived glycan shielding of the trimeric Env spike, its only surface neutralization target. The Env trimer apex is an especially attractive vaccine target because broadly neutralizing antibodies (bNAbs) from humans and non-human primates can penetrate this glycan barrier using long, negatively charged HCDR3 loops that contact the V2 C-strand together with the surrounding glycans. 2,3 Compared with several other HIV bNAb classes, some apex-directed lineages may achieve neutralization breadth with relatively lower levels of somatic hypermutation, making them conceptually attractive for vaccine induction. 1,4 However, infection-derived apex antibody maturation occurs during prolonged viral replication and Env-antibody co-evolution, whereas a recombinant subunit vaccine must reproduce key selection steps using de fi ned immunogens, adjuvants, and antigen-display geometry. Therefore, the central question is whether vaccination alone can generate infection-like apex antibodies capable of neutralizing diverse clinical isolates. 1 The study addresses this question through rational immunogen selection and antigen display strategies. The authors screened near-native, cleavage-independent NFL-stabilized