Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions
Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions
Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.
HIV antibodies, HIV seropositivity, HIV-1/genetics, animals, antibodies, neutralizing, broadly neutralizing antibodies, mice, vaccination, insertions, mouse model, deletions, vaccines, neutralizing antibodies, bNAbs, germline-targeting, NGS, HIV-1 Env
101003
Caniels, Tom G.
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Medina-Ramírez, Max
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Zhang, Jinsong
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Sarkar, Anita
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Kumar, Sonu
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LaBranche, Alex
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Derking, Ronald
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Allen, Joel D.
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Snitselaar, Jonne L.
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Capella-Pujol, Joan
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Sánchez, Iván Del Moral
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Yasmeen, Anila
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Diaz, Marilyn
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Aldon, Yoann
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Bijl, Tom P L.
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Venkatayogi, Sravani
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Martin Beem, Joshua S.
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Newman, Amanda
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Jiang, Chuancang
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Lee, Wen-Hsin
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Pater, Maarten
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Burger, Judith A.
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van Breemen, Mariëlle J.
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de Taeye, Steven W.
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Rantalainen, Kimmo
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LaBranche, Celia
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Saunders, Kevin O.
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Montefiori, David
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Ozorowski, Gabriel
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Ward, Andrew B.
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Crispin, Max
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Moore, John P.
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Klasse, Per Johan
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Haynes, Barton F.
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Wilson, Ian A.
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Wiehe, Kevin
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Verkoczy, Laurent
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Sanders, Rogier W.
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18 April 2023
Caniels, Tom G.
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Medina-Ramírez, Max
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Zhang, Jinsong
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Sarkar, Anita
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Kumar, Sonu
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LaBranche, Alex
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Derking, Ronald
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Allen, Joel D.
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Snitselaar, Jonne L.
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Capella-Pujol, Joan
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Sánchez, Iván Del Moral
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Yasmeen, Anila
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Diaz, Marilyn
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Aldon, Yoann
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Bijl, Tom P L.
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Venkatayogi, Sravani
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Martin Beem, Joshua S.
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Newman, Amanda
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Jiang, Chuancang
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Lee, Wen-Hsin
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Pater, Maarten
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Burger, Judith A.
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van Breemen, Mariëlle J.
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de Taeye, Steven W.
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Rantalainen, Kimmo
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LaBranche, Celia
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Saunders, Kevin O.
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Montefiori, David
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Ozorowski, Gabriel
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Ward, Andrew B.
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Crispin, Max
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Moore, John P.
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Klasse, Per Johan
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Haynes, Barton F.
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Wilson, Ian A.
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Wiehe, Kevin
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Verkoczy, Laurent
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Sanders, Rogier W.
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