EMD-24853
Modified BG505 SOSIP-based immunogen RC1 in complex with elicited mAb Ab283MUR Fab and 8ANC195 Fab
EMD-24853
Single-particle5.2 Å
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Map released: 06/04/2022
Last modified: 06/04/2022
Sample Organism:
Mus musculus,
Human immunodeficiency virus 1,
Homo sapiens
Sample: Elicited Ab283MUR Fab in complex with RC1 SOSIP and bNAb 8ANC195 Fab
Deposition Authors: Abernathy ME
,
Bjorkman PJ
Sample: Elicited Ab283MUR Fab in complex with RC1 SOSIP and bNAb 8ANC195 Fab
Deposition Authors: Abernathy ME
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Sequential immunization of macaques elicits heterologous neutralizing antibodies targeting the V3-glycan patch of HIV-1 Env.
Escolano A
,
Gristick HB
,
Gautam R
,
DeLaitsch AT
,
Abernathy ME
,
Yang Z
,
Wang H
,
Hoffmann MAG
,
Nishimura Y
,
Wang Z
,
Koranda N,
Kakutani LM
,
Gao H,
Gnanapragasam PNP,
Raina H
,
Gazumyan A
,
Cipolla M
,
Oliveira TY
,
Ramos V
,
Irvine DJ
,
Silva M
,
West Jr AP
,
Keeffe JR
,
Barnes CO
,
Seaman MS
,
Nussenzweig MC
,
Martin MA
,
Bjorkman PJ
(2021) Sci Transl Med , 13 , eabk1533 - eabk1533
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(2021) Sci Transl Med , 13 , eabk1533 - eabk1533
Abstract:
Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus and antibody coevolution. Previous studies showed that sequential immunization with a V3-glycan patch germline-targeting HIV-1 envelope trimer (Env) followed by variant Envs can reproduce this process in mice carrying V3-glycan bNAb precursor B cells. However, eliciting bNAbs in animals with polyclonal antibody repertoires is more difficult. We used a V3-glycan immunogen multimerized on virus-like particles (VLPs), followed by boosting with increasingly native-like Env-VLPs, to elicit heterologous neutralizing antibodies in nonhuman primates (NHPs). Structures of antibody/Env complexes after prime and boost vaccinations demonstrated target epitope recognition with apparent maturation to accommodate glycans. However, we also observed increasing off-target antibodies with boosting. Eight vaccinated NHPs were subsequently challenged with simian-human immunodeficiency virus (SHIV), and seven of eight animals became infected. The single NHP that remained uninfected after viral challenge exhibited one of the lowest neutralization titers against the challenge virus. These results demonstrate that more potent heterologous neutralization resulting from sequential immunization is necessary for protection in this animal model. Thus, improved prime-boost regimens to increase bNAb potency and stimulate other immune protection mechanisms are essential for developing anti–HIV-1 vaccines.
Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus and antibody coevolution. Previous studies showed that sequential immunization with a V3-glycan patch germline-targeting HIV-1 envelope trimer (Env) followed by variant Envs can reproduce this process in mice carrying V3-glycan bNAb precursor B cells. However, eliciting bNAbs in animals with polyclonal antibody repertoires is more difficult. We used a V3-glycan immunogen multimerized on virus-like particles (VLPs), followed by boosting with increasingly native-like Env-VLPs, to elicit heterologous neutralizing antibodies in nonhuman primates (NHPs). Structures of antibody/Env complexes after prime and boost vaccinations demonstrated target epitope recognition with apparent maturation to accommodate glycans. However, we also observed increasing off-target antibodies with boosting. Eight vaccinated NHPs were subsequently challenged with simian-human immunodeficiency virus (SHIV), and seven of eight animals became infected. The single NHP that remained uninfected after viral challenge exhibited one of the lowest neutralization titers against the challenge virus. These results demonstrate that more potent heterologous neutralization resulting from sequential immunization is necessary for protection in this animal model. Thus, improved prime-boost regimens to increase bNAb potency and stimulate other immune protection mechanisms are essential for developing anti–HIV-1 vaccines.