A challenge for HIV-1 immunogen design is inducing neutralizing antibodies (NAbs) against neutralization-resistant (Tier-2) viruses that dominate human transmissions. We show that a soluble recombinant HIV-1 envelope glycoprotein trimer that adopts a native conformation (BG505 SOSIP.664) induced NAbs potently against the sequence-matched Tier-2 virus in rabbits and similar but weaker responses in macaques. The trimer also consistently induced cross-reactive NAbs against more sensitive (Tier-1) viruses. Tier-2 NAbs recognized conformational epitopes that differed between animals and in some cases overlapped with those recognized by broadly neutralizing antibodies (bNAbs), whereas Tier-1 responses targeted linear V3 epitopes. A second trimer, B41 SOSIP.664, also induced a strong autologous Tier-2 NAb response in rabbits. Thus, native-like trimers represent a promising starting point for developing HIV-1 vaccines aimed at inducing bNAbs.

Summary The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers, but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs.

The envelope glycoprotein trimer (Env) on the surface of HIV-1 recognizes CD4+ T cells and mediates viral entry. During this process, Env undergoes large conformational rearrangements making it difficult to study in its native state. Soluble, stabilized trimers have provided valuable insights into Env structure, but they lack the hydrophobic membrane proximal external region (MPER), which is an important target of broadly neutralizing antibodies (bnAbs), the transmembrane domain and the cytoplasmic tail (CT). Here we present a 4.2 Å resolution cryoEM structure of a clade B virus Env lacking only the cytoplasmic tail (EnvΔCT) and stabilized by the bnAb PGT151, and an 8.8 Å resolution reconstruction of EnvΔCT in complex with PGT151 and MPER-targeting antibody 10E8. These structures provide new insights into the wild-type Env structure.