Molecular insights into antibody-mediated protection against the prototypic simian immunodeficiency virus

Abstract

SIVmac239 infection of macaques is a favored model of human HIV infection. However, the SIVmac239 envelope (Env) trimer structure, glycan occupancy, and the targets and ability of neutralizing antibodies (nAbs) to protect against SIVmac239 remain unknown. Here, we report the isolation of SIVmac239 nAbs that recognize a glycan hole and the V1/V4 loop. A high-resolution structure of a SIVmac239 Env trimer-nAb complex shows many similarities to HIV and SIVcpz Envs, but with distinct V4 features and an extended V1 loop. Moreover, SIVmac239 Env has a higher glycan shield density than HIV Env that may contribute to poor or delayed nAb responses in SIVmac239-infected macaques. Passive transfer of a nAb protects macaques from repeated intravenous SIVmac239 challenge at serum titers comparable to those described for protection of humans against HIV infection. Our results provide structural insights for vaccine design and shed light on antibody-mediated protection in the SIV model.

Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge

“…Two cryo-electron microscopy structures of the SIV mac 239 Env trimer were recently solved [ 37 , 40 ], one of which was determined for PGT145 in complex with an Env variant (SIV mac 239 Env:K180T) with a lysine-to-threonine (K180T) substitution that stabilizes the binding of this antibody to SIV Env similar to our K180S substitution [ 32 , 40 ]. This structure reveals extensive asymmetric contacts between PGT145 and the N171 glycans on each of the three gp120 protomers, primarily involving the complementarity determining region 3 and 1 of the heavy and light chains (CDRH3 and CDRL1) ( Fig 5A ).…”

Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge

“…To investigate this possibility, serial dilutions of the SIV mac 239 K180S challenge stock were incubated with 50 µg/ml of PGT145 and K11 before the addition of TZM-bl cells. In contrast to K11, which binds to a glycan hole on the gp120 surface of the SIV Env trimer and completely neutralizes SIV mac 239 K180S at high multiplicities of infection [37], residual infectivity became detectable at a 10-fold virus dilution (1.4 ng/ml p27) in the presence of PGT145 ( S1 Fig. ).…”

“…Two cryo-electron microscopy structures of the SIV mac 239 Env trimer were recently solved [37, 40], one of which was determined for PGT145 in complex with an Env variant (SIV mac 239 Env:K180T) with a lysine-to-threonine (K180T) substitution that stabilizes the binding of this antibody to SIV Env similar to our K180S substitution [32, 40]. This structure reveals extensive asymmetric contacts between PGT145 and the N171 glycans on each of the three gp120 protomers, primarily involving the complementarity determining region 3 and 1 of the heavy and light chain, respectively (CDRH3 and CDRL1) ( Fig.…”

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV replication in M3+ Mauritian cynomolgus macaques initiated on ART two weeks post-infection

“…While neutralizing antibodies against HIV have been associated with viral control, macaques rarely generate potent neutralizing antibodies against SIVmac239 [ 52 ]. Neutralizing antibodies against SIVmac239 have been identified [ 53 , 54 ], but are uncommon. We cannot discount the possibility that neutralizing antibodies were involved in virus suppression, but we only evaluated env-binding antibodies in the present study.…”