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HIV broadly neutralizing antibodies: learning lessons from infections Penny Moore National Institute for Communicable Diseases, a division of the National.

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Presentation on theme: "HIV broadly neutralizing antibodies: learning lessons from infections Penny Moore National Institute for Communicable Diseases, a division of the National."— Presentation transcript:

1 HIV broadly neutralizing antibodies: learning lessons from infections Penny Moore National Institute for Communicable Diseases, a division of the National Health Laboratory Service of South Africa, University of the Witwatersrand, Johannesburg, South Africa and the Centre for the AIDS Program of Research in South Africa (CAPRISA) IAS, 2014, Melbourne

2 Broadly neutralizing antibodies (BNAbs) develop in a fifth of HIV infected people Elite neutralizers (1%) Broad neutralizers (20%) No/limited breadth Screening of chronically infected people shows BCN antibodies develop fairly often...

3 V2/glycan >12 mAbs V3/glycan supersite >25 mAbs CD4bs >25 mAbs MPER >5 mAbs Modified from Burton et al., Science 2012 Isolation of monoclonal anti-HIV antibodies We know (most of) the targets gp120-gp41 interface >3 mAbs

4 Ontogeny of BNAbs: How do BNAbs develop? years of infection Breadth UCA (unmutated common ancestor)

5 years of infection Breadth UCA Ontogeny of BNAbs: How do BNAbs develop?

6 years of infection Breadth UCA Ontogeny of BNAbs: How do BNAbs develop?

7 V2/glycan >12 mAbs V3/glycan >25 mAbs CD4bs >25 mAbs MPER >5 mAbs Modified from Burton et al., Science 2012 Long CDRH3 (>25 aa) to penetrate glycan shield Heavily mutated (30%) Developmental pathways are likely to differ by epitope

8 V2/glycan >12 mAbs V3/glycan >25 mAbs CD4bs >25 mAbs MPER >5 mAbs Modified from Burton et al., Science 2012 Heavily mutated (30%) Developmental pathways are likely to differ by epitope

9 Highly mutated away from their ancestor CD4bs BNAbs – highly affinity matured years of infection Mature BNAb Unmutated common ancestor

10 V2/glycan >12 mAbs V3/glycan >25 mAbs MPER >5 mAbs Modified from Burton et al., Science 2012 Long CDRH3 (>25 aa) to penetrate glycan shield Do long CDR H3s similarly develop gradually?

11 CAP256 Gray et al 2011, Moore et al 2011 CAP256 targets V2

12 Twelve related mAbs isolated by B cell culture Doria-Rose, Schramm, Gorman, Moore et al, Nature, 2014 Weeks post-infection V1V2-directed NAbs * 206 WeekAntibody Somatic mutations (nt) CDR H3 length (aa) Neutralization (46 strains) V 1-51*02 VH3-30*18Breadth Potency (IC 50, μg/ml) 59CAP256-VRC %8.3%35 15% CAP256-VRC %8.7%35 17%0.40 CAP256-VRC %8.7%35 30%0.06 CAP256-VRC %9.0%35 28%0.25 CAP256-VRC %10.1%35 22%0.10 CAP256-VRC %10.8%36 15%0.16 CAP256-VRC %11.8%35 13%2.02 CAP256-VRC %11.8%37 46%0.14 CAP256-VRC %14.2%37 46% CAP256-VRC %11.8%35 24%0.60 CAP256-VRC %11.9%35 24%0.82 CAP256-VRC %15.3%35 7%0.49 Neutralization breadth starts

13 CAP256-VRC26 has typical features of anti-V2 broad neutralizing antibodies HL Kim, A Cupo, R Sanders, IA Wilson, JP Moore, AB Ward Antibody BG505 SOSIP HIV Env Ideal for defining the developmental pathways of V2 antibodies with long CDR H3 Jason Gorman and Peter Kwong PG9 CAP256-VRC26

14 CAP256-VRC26 heavy chain and light chain antibody sequences CAP256-VRC26.01 CAP256-VRC26.10 CAP256-VRC26.11 CAP256-VRC26.06 CAP256-VRC26.05 CAP256-VRC26.02 CAP256-VRC26.04 CAP256-VRC26.03 CAP256-VRC26.07 CAP256-VRC26.12 CAP256-VRC26.09 CAP256-VRC26.08 VH3-30*18 VL1-52*02 UCA_H UCA_L Heavy Chain longitudinal phylogenetic tree Week Evolutionary distance 0.02 Chaim Schramm and Larry Shapiro Light Chain longitudinal phylogenetic tree The UCA had a 35 amino acid CDR H3 fully formed through VDJ recombination.

15 Long CDRH3s The CAP256-VRC26 unmutated common ancestor had a fully formed long CDR H3 Unmutated common ancestor Mature BNAb

16 Long CDRH3s The CAP256-VRC26 unmutated common ancestor had a fully formed long CDR H3 Was this enough for breadth? Mature BNAb Unmutated common ancestor

17 Development of CAP256-VRC26.01 Nicole Doria-Rose, Ryan Staupe, Nancy Longo, Jinal Bhiman Weeks post-infection V1V2-directed NAbs * 206 WeekAntibody Somatic mutations (nt) CDR H3 length (aa) Neutralization (46 strains) V 1-51*02 VH3-30*18Breadth Potency (IC 50, μg/ml) 59CAP256-VRC %8.3%35 15% CAP256-VRC %8.7%35 17%0.40 CAP256-VRC %8.7%35 30%0.06 CAP256-VRC %9.0%35 28%0.25 CAP256-VRC %10.1%35 22%0.10 CAP256-VRC %10.8%36 15%0.16 CAP256-VRC %11.8%35 13%2.02 CAP256-VRC %11.8%37 46%0.14 CAP256-VRC %14.2%37 46% CAP256-VRC %11.8%35 24%0.60 CAP256-VRC %11.9%35 24%0.82 CAP256-VRC %15.3%35 7%0.49 Neutralization breadth starts

18 Rapid development of neutralization breadth within the CAP256-VRC26 lineage Chaim Schramm VRC26-I1VRC26-UCAVRC26-I2VRC26.01

19 Rapid development of neutralization breadth within the CAP256-VRC26 lineage VRC26-I1VRC26-UCAVRC26-I2VRC26.01 The CAP256-VRC26 UCA, despite having a long CDR H3, can ONLY neutralize the virus that infected CAP256 - no neutralization breadth CAP256 SI

20 Rapid development of neutralization breadth within the CAP256-VRC26 lineage Chaim Schramm VRC26-I1VRC26-UCAVRC26-I2VRC26.01 CAP256 SII

21 Only moderate levels of somatic hypermutation needed for breadth Breadth years of infection ✗ Weeks…. Unmutated common ancestor Mature BNAb with moderate somatic hypermutation

22 years of infection Breadth UCA Ontogeny of BNAbs: Looking backwards from breadth

23 Dramatic viral changes immediately precede CAP256 neutralization breadth CAP256-VRC26 emerges in peripheral B cell repertoire Maturation of the anti-V2 lineage CAP256-VRC26 was associated with viral replacement in the epitope Broadly neutralizing antibodies emerge in the context of multiple immunotypes created through viral diversification Duration of infection V1V2 mutations

24 Maturation of the anti-V2 lineage CAP256-VRC26 was associated with viral replacement in the epitope Broadly neutralizing antibodies emerge in the context of multiple immunotypes created through viral diversification Dramatic viral changes immediately precede CAP256 neutralization breadth CAP256-VRC26 emerges in peripheral B cell repertoire Plasma heterologous neutralization develops V1V2 mutations Jinal Bhiman, Daniel Sheward, Molati Nonyane, Bronwen Lambson Duration of infection

25 R166, a crucial part of the CAP256 epitope, undergoes selection pressure as bNAbs mature CAP256 infecting virus weeks p.i. Emergence of escape mutations drives increased breadth Jinal Bhiman, Daniel Sheward

26 weeks p.i. 166 All subtype C viruses (n=1,005) Emergence of new immunotypes drives increased breadth – K166 CAP256 infecting virus

27 weeks p.i. 166 All subtype C viruses (n=1,005) Emergence of new immunotypes drives increased breadth – K166 CAP256 infecting virus CAP256 CAP256 R166K Percent breadth

28  Isolated PG9-type V1V2 neutralizing mAbs from seroconverting donor CAP256  CAP256 mAbs have a characteristic long anionic CDRH3 formed by initial gene recombination; i.e., present on naïve BCR  The UCA was capable of strain-specific neutralization, with modest affinity maturation conferring breadth  Viral diversification and co-evolution was associated with breadth, through bNAb tolerance of escape mutations Summary Doria-Rose, Schramm, Gorman, Moore et al, Nature, 2014

29 V1V2 - Long CDRH3s CD4bs - highly mutated away from their ancestor Which pathway is more amenable to HIV vaccine design?  Requires the engagement of a BCR with a long CDR H3 - these B cells are very rare  Once stimulated, V1V2 BNAbs can develop within months, not years  Immunogens may need to recreate antigenic diversity to drive affinity maturation  No requirement for long CDR H3, but Ig allele skewing may limit viable BCRs  May need high levels of affinity maturation take years – hard to achieve through vaccination

30 Acknowledgements Participant CAP256 Slim Abdool Karim, Quarraisha Abdool Karim, Nigel Garrett and the CAPRISA staff Mascola lab Nicole Doria-Rose R. Staupe, R. Roark M. Ernandes Rebecca Lynch Rui Kong Nancy Longo Sijy O’Dell Stephen Schmidt Krisha McKee Mark Louder John Mascola Bioinformatics Chaim Schramm Zhenhai Zhang Cinque Soto Ivelin Georgiev Larry Shapiro Williamson lab Daniel Sheward Carolyn Williamson Kwong lab Jason Gorman Marie Pancera Tongqing Zhou Baoshan Zhang Ivelin Georgiev Young Do Kwon Yongping Yang Peter Kwong NIH Sequencing Core Holly Coleman Brian Schmidt Morgan Park Jim Mullikin NIAID NVITAL Ellen Turk Bob Bailer IAVI NAC, CHAVI-ID and Scripps Andrew Ward Helen Kim Albert Cupo John Moore Rogier Sanders Wayne Koff Ian Wilson Dennis Burton Torrey Pines Emma Crooks James Binley U. Texas Austin Brandon DeKosky George Georgiou NICD Jinal Bhiman Kurt Wibner Molati Nonyane Bronwen Lambson Thandeka Khoza Mashudu Madzivhandila Lynn Morris


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