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TitleSequential immunization of macaques elicits heterologous neutralizing antibodies targeting the V3-glycan patch of HIV-1 Env.
Journal, issue, pagesSci Transl Med, Vol. 13, Issue 621, Page eabk1533, Year 2021
Publish dateNov 24, 2021
AuthorsAmelia Escolano / Harry B Gristick / Rajeev Gautam / Andrew T DeLaitsch / Morgan E Abernathy / Zhi Yang / Haoqing Wang / Magnus A G Hoffmann / Yoshiaki Nishimura / Zijun Wang / Nicholas Koranda / Leesa M Kakutani / Han Gao / Priyanthi N P Gnanapragasam / Henna Raina / Ana Gazumyan / Melissa Cipolla / Thiago Y Oliveira / Victor Ramos / Darrell J Irvine / Murillo Silva / Anthony P West / Jennifer R Keeffe / Christopher O Barnes / Michael S Seaman / Michel C Nussenzweig / Malcolm A Martin / Pamela J Bjorkman /
PubMed AbstractBroadly 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- ...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.
External linksSci Transl Med / PubMed:34818054 / PubMed Central
MethodsEM (single particle)
Resolution4.5 - 18.4 Å
Structure data

EMDB-24853: Modified BG505 SOSIP-based immunogen RC1 in complex with elicited mAb Ab283MUR Fab and 8ANC195 Fab
Method: EM (single particle) / Resolution: 5.2 Å

EMDB-24854: Modified BG505 SOSIP-based immunogen RC1 in complex with elicited mAb Ab1170NHP Fab and 8ANC195 Fab
Method: EM (single particle) / Resolution: 4.5 Å

EMDB-24855: Modified BG505 SOSIP-based immunogen RC1 in complex with Rabbit 2249 post-Prime polyclonal Fabs
Method: EM (single particle) / Resolution: 18.4 Å

EMDB-24856: Modified BG505 SOSIP-based immunogen RC1 in complex with Rabbit 2249 post-Boost 1 polyclonal Fabs
Method: EM (single particle) / Resolution: 15.0 Å

EMDB-24857: Modified BG505 SOSIP-based immunogen RC1 in complex with Rabbit 2249 post-Boost 2 polyclonal Fabs
Method: EM (single particle) / Resolution: 16.0 Å

EMDB-24858: Modified BG505 SOSIP-based immunogen RC1 in complex with Rabbit 2249 post-Boost 3 polyclonal Fabs
Method: EM (single particle) / Resolution: 15.0 Å

EMDB-24859: Modified BG505 SOSIP-based immunogen RC1 in complex with Rabbit 2249 post-Boost 4 polyclonal Fabs
Method: EM (single particle) / Resolution: 15.0 Å

EMDB-24860: Modified BG505 SOSIP-based immunogen RC1 in complex with NHP 1 post-Prime polyclonal Fabs
Method: EM (single particle) / Resolution: 17.0 Å

EMDB-24861: Modified BG505 SOSIP-based immunogen RC1 in complex with NHP 1 post-Boost 1 polyclonal Fabs
Method: EM (single particle) / Resolution: 17.0 Å

Source
  • Mus musculus (house mouse)
  • Human immunodeficiency virus 1
  • Homo sapiens (human)
  • Macaca mulatta (Rhesus monkey)
  • Oryctolagus cuniculus (rabbit)

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