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TitleProfiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy.
Journal, issue, pagesNat Immunol, Vol. 26, Issue 11, Page 2016-2029, Year 2025
Publish dateOct 6, 2025
AuthorsLutz Gieselmann / Andrew T DeLaitsch / Malena Rohde / Henning Gruell / Christoph Kreer / Meryem Seda Ercanoglu / Harry B Gristick / Philipp Schommers / Elvin Ahmadov / Caelan Radford / Andrea Mazzolini / Lily Zhang / Anthony P West / Johanna Worczinski / Anna Momot / Maren L Reichwein / Jacqueline Knüfer / Ricarda Stumpf / Nonhlanhla N Mkhize / Haajira Kaldine / Sinethemba Bhebhe / Sharvari Deshpande / Federico Giovannoni / Erin Stefanutti / Fabio Benigni / Colin Havenar-Daughton / Davide Corti / Arne Kroidl / Anurag Adhikari / Aubin J Nanfack / Georgia E Ambada / Ralf Duerr / Lucas Maganga / Wiston William / Nyanda E Ntinginya / Timo Wolf / Christof Geldmacher / Michael Hoelscher / Clara Lehmann / Penny L Moore / Thierry Mora / Aleksandra M Walczak / Peter B Gilbert / Nicole A Doria-Rose / Yunda Huang / Jesse D Bloom / Michael S Seaman / Pamela J Bjorkman / Florian Klein /
PubMed AbstractAdministration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we ...Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a V1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml, breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml, breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.
External linksNat Immunol / PubMed:41053396 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.75 - 3.8 Å
Structure data

42363

8ulr

EMDB-42363, PDB-8ulr:
Cryo-EM structure of the BG505 SOSIPv2 in complex with bNAb 05_B08 Fabs
Method: EM (single particle) / Resolution: 3.3 Å

42364

8uls

EMDB-42364, PDB-8uls:
Cryo-EM structure of the BG505 SOSIPv2 in complex with bNAb 01_D03 Fabs
Method: EM (single particle) / Resolution: 3.2 Å

42365

8ult

EMDB-42365, PDB-8ult:
Cryo-EM structure of the BG505 SOSIPv2 in complex with bNAb 04_A06 Fabs
Method: EM (single particle) / Resolution: 3.8 Å

42366

8ulu

EMDB-42366, PDB-8ulu:
Cryo-EM structure of the BG505 SOSIPv2 in complex with bNAb 04_A06 and PGDM1400 Fabs
Method: EM (single particle) / Resolution: 3.8 Å

46649

9d8v

EMDB-46649, PDB-9d8v:
Cryo-EM structure of the BG505 SOSIPv2
Method: EM (single particle) / Resolution: 2.9 Å

PDB-8uki:
Crystal structure of 04_A06 Fab
Method: X-RAY DIFFRACTION / Resolution: 1.75 Å

Chemicals

ChemComp-HOH:
WATER

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • human immunodeficiency virus 1
KeywordsIMMUNE SYSTEM / Fab / broadly neutralizing antibody / HIV-1 / CD4 binding site / Viral Protein/Immune System / ANTIBODY / CD4-BINDING SITE / IMMUNE COMPLEX / Viral Protein-Immune System complex / VIRAL PROTEIN / Envelope / SOSIP

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