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TitlemRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies.
Journal, issue, pagesScience, Vol. 384, Issue 6697, Page eadk0582, Year 2024
Publish dateMay 17, 2024
AuthorsZhenfei Xie / Ying-Cing Lin / Jon M Steichen / Gabriel Ozorowski / Sven Kratochvil / Rashmi Ray / Jonathan L Torres / Alessia Liguori / Oleksandr Kalyuzhniy / Xuesong Wang / John E Warner / Stephanie R Weldon / Gordon A Dale / Kathrin H Kirsch / Usha Nair / Sabyasachi Baboo / Erik Georgeson / Yumiko Adachi / Michael Kubitz / Abigail M Jackson / Sara T Richey / Reid M Volk / Jeong Hyun Lee / Jolene K Diedrich / Thavaleak Prum / Samantha Falcone / Sunny Himansu / Andrea Carfi / John R Yates / James C Paulson / Devin Sok / Andrew B Ward / William R Schief / Facundo D Batista /
PubMed AbstractGermline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells ...Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody-induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan-targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses. The delivery of the prime and boost immunogens as messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, and affinity maturation and may be an effective tool in HIV vaccine development.
External linksScience / PubMed:38753770
MethodsEM (single particle)
Resolution3.14 - 30.0 Å
Structure data

28941

8f92

EMDB-28941, PDB-8f92:
HIV Env BG505_MD39_B11 SOSIP boosting trimer in complex with B11_d77.7 mouse Fab and RM20A3 Fab
Method: EM (single particle) / Resolution: 3.14 Å

28942

8f9g

EMDB-28942, PDB-8f9g:
HIV Env germline targeting BG505_MD64_N332-GT5 SOSIP in complex with V3-glycan polyclonal Fab isolated from immunized BG18HCgl knock-in mice
Method: EM (single particle) / Resolution: 3.2 Å

28945

8f9m

EMDB-28945, PDB-8f9m:
HIV Env germline targeting BG505_MD64_N332-GT5 SOSIP in complex with V3-glycan polyclonal Fab isolated from immunized wild type mice, and NHP monoclonal Fab RM20A3
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-29330: N332-GT5 SOSIP in complex with base polyclonal Fabs isolated at day 42 from protein immunized wild type mice
Method: EM (single particle) / Resolution: 28.0 Å

EMDB-29333: N332-GT5 SOSIP in complex with base polyclonal Fabs isolated at day 42 from protein immunized BG18HCgl knock-in mice
Method: EM (single particle) / Resolution: 28.0 Å

EMDB-29334: N332-GT5 SOSIP in complex with V1V3 polyclonal Fabs isolated at day 16 from mRNA immunized wild type mice
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-29335: N332-GT5 SOSIP in complex with V1V3 polyclonal Fabs isolated at day 42 from mRNA immunized BG18HCgl knock-in mice
Method: EM (single particle) / Resolution: 30.0 Å

43190

8vfv

EMDB-43190, PDB-8vfv:
HIV Env BG505_MD39_B16 SOSIP boosting trimer in complex with B16_d77.5 mouse Fab and RM20A3 Fab
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43191: N332-GT5 SOSIP in complex with V1V3 polyclonal Fabs isolated at day 14 from N332-GT2 nanoparticle-immunized BG18HCgl knock-in mice
Method: EM (single particle) / Resolution: 22.0 Å

EMDB-43192: N332-GT5 SOSIP in complex with V1V3 polyclonal Fabs isolated at day 15 from N332-GT5 nanoparticle-immunized BG18HCgl knock-in mice
Method: EM (single particle) / Resolution: 23.0 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • human immunodeficiency virus
  • macaca mulatta (Rhesus monkey)
  • mus musculus (house mouse)
  • synthetic construct (others)
  • human immunodeficiency virus 1
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / mouse antibody / germline targeting / HIV-1 / vaccine design / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / polyclonal

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