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
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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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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