HIV broadly neutralizing antibodies: learning lessons from infections Penny Moore National Institute for Communicable Diseases, a division of the National.
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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
big
bigger
biggest
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...
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 antibodiesWe know (most of) the targets
gp120-gp41
interface>3 mAbs
Ontogeny of BNAbs: How do BNAbs develop?
years of infection
Breadth
UCA(unmutated
common ancestor)
years of infection
Breadth
UCA
Ontogeny of BNAbs: How do BNAbs develop?
years of infection
Breadth
UCA
Ontogeny of BNAbs: How do BNAbs develop?
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
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
Highly mutated away from their ancestor
CD4bs BNAbs – highly affinity matured
years of infection
Mature BNAb
Unmutated common ancestor
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?
CAP256
Gray et al 2011, Moore et al 2011
Western Cape
Eastern Cape
Northern Cape
North West
Free State
Northern Province
Gauteng
KwaZuluNatal
Mpumalanga
Durban
Vulindlela
CAP256 targets V2
Twelve related mAbs isolated by B cell culture
Doria-Rose, Schramm, Gorman, Moore et al, Nature, 2014
Weeks post-infection
V1V2-directedNAbs
15 30 38 48 59 119 176* 206
Week Antibody
Somatic mutations (nt)CDR H3 length (aa)
Neutralization (46 strains)
Vl1-51*02 VH3-30*18 BreadthPotency
(IC50, μg/ml)
59 CAP256-VRC26.01 3.9% 8.3% 35 15% 2.93
119
CAP256-VRC26.02 4.9% 8.7% 35 17% 0.40CAP256-VRC26.03 7.4% 8.7% 35 30% 0.06CAP256-VRC26.04 8.1% 9.0% 35 28% 0.25CAP256-VRC26.05 5.4% 10.1% 35 22% 0.10CAP256-VRC26.06 7.4% 10.8% 36 15% 0.16CAP256-VRC26.07 7.7% 11.8% 35 13% 2.02CAP256-VRC26.08 9.8% 11.8% 37 46% 0.14CAP256-VRC26.09 9.8% 14.2% 37 46% 0.08
206CAP256-VRC26.10 3.9% 11.8% 35 24% 0.60CAP256-VRC26.11 13.7% 11.9% 35 24% 0.82CAP256-VRC26.12 8.4% 15.3% 35 7% 0.49
Neutralization breadth starts
CAP256-VRC26 has typical features of anti-V2 broad neutralizing antibodies
HL Kim, A Cupo, R Sanders, IA Wilson, JP Moore, AB Ward
Antibody
BG505SOSIP HIV Env
Ideal for defining the developmental pathways of V2 antibodies with long CDR H3
Jason Gorman and Peter Kwong
PG9 CAP256-VRC26
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
Week38
48
59
119
176
206
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.
Long CDRH3s
The CAP256-VRC26 unmutated common ancestor had a fully formed long CDR H3
Unmutated common ancestor
Mature BNAb
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
Development of CAP256-VRC26.01
Nicole Doria-Rose, Ryan Staupe, Nancy Longo, Jinal Bhiman
Weeks post-infection
V1V2-directedNAbs
15 30 38 48 59 119 176* 206
Week Antibody
Somatic mutations (nt)CDR H3 length (aa)
Neutralization (46 strains)
Vl1-51*02 VH3-30*18 BreadthPotency
(IC50, μg/ml)
59 CAP256-VRC26.01 3.9% 8.3% 35 15% 2.93
119
CAP256-VRC26.02 4.9% 8.7% 35 17% 0.40CAP256-VRC26.03 7.4% 8.7% 35 30% 0.06CAP256-VRC26.04 8.1% 9.0% 35 28% 0.25CAP256-VRC26.05 5.4% 10.1% 35 22% 0.10CAP256-VRC26.06 7.4% 10.8% 36 15% 0.16CAP256-VRC26.07 7.7% 11.8% 35 13% 2.02CAP256-VRC26.08 9.8% 11.8% 37 46% 0.14CAP256-VRC26.09 9.8% 14.2% 37 46% 0.08
206CAP256-VRC26.10 3.9% 11.8% 35 24% 0.60CAP256-VRC26.11 13.7% 11.9% 35 24% 0.82CAP256-VRC26.12 8.4% 15.3% 35 7% 0.49
Neutralization breadth starts
Rapid development of neutralization breadth within the CAP256-VRC26 lineage
Chaim Schramm
VRC26-I1VRC26-UCA VRC26-I2 VRC26.01
Rapid development of neutralization breadth within the CAP256-VRC26 lineage
VRC26-I1VRC26-UCA VRC26-I2 VRC26.01
The CAP256-VRC26 UCA, despite having a long CDR H3, can ONLY neutralize the virus that infected CAP256 - no neutralization breadth
CAP256 SI
Rapid development of neutralization breadth within the CAP256-VRC26 lineage
Chaim Schramm
VRC26-I1VRC26-UCA VRC26-I2 VRC26.01
CAP256 SII
Only moderate levels of somatic hypermutation needed for breadth
BreadthBreadth
years of infection ✗Weeks….Unmutated
common ancestor
Mature BNAb with moderate
somatic hypermutation
years of infection
Breadth
UCA
Ontogeny of BNAbs: Looking backwards from breadth
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
Dur
ation
of i
nfec
tion
160-171
V1V2 mutations
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
160-171
V1V2 mutations
Jinal Bhiman, Daniel Sheward, Molati Nonyane, Bronwen Lambson
Dur
ation
of i
nfec
tion
R166, a crucial part of the CAP256 epitope, undergoes selection pressure as bNAbs
mature
CAP256 infecting
virus
166
94 weeks
p.i.
Emergence of escape mutations drives increased breadth
Jinal Bhiman, Daniel Sheward
166
94 weeks
p.i.
166
All subtype C viruses (n=1,005)
Emergence of new immunotypes drives increased breadth – K166
CAP256 infecting
virus
166
94 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
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
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
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
Acknowledgements Participant CAP256
Slim Abdool Karim, Quarraisha Abdool Karim, Nigel Garrett and the CAPRISA staff
Mascola labNicole Doria-RoseR. Staupe, R. RoarkM. ErnandesRebecca Lynch Rui KongNancy LongoSijy O’DellStephen SchmidtKrisha McKeeMark LouderJohn Mascola
BioinformaticsChaim SchrammZhenhai ZhangCinque SotoIvelin GeorgievLarry Shapiro
Williamson labDaniel ShewardCarolyn Williamson
Kwong labJason GormanMarie PanceraTongqing ZhouBaoshan ZhangIvelin GeorgievYoung Do KwonYongping YangPeter Kwong
NIH Sequencing CoreHolly ColemanBrian SchmidtMorgan ParkJim Mullikin
NIAID NVITALEllen TurkBob Bailer
IAVI NAC, CHAVI-ID and ScrippsAndrew WardHelen KimAlbert CupoJohn MooreRogier SandersWayne KoffIan WilsonDennis Burton
Torrey PinesEmma CrooksJames Binley
U. Texas AustinBrandon DeKoskyGeorge Georgiou
NICDJinal BhimanKurt WibnerMolati NonyaneBronwen LambsonThandeka KhozaMashudu MadzivhandilaLynn Morris
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