HIV-1 Antibodies

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CD4 gp120trimer

Helper T-cell

MembraneCCR40co-receptor

HIV-1 Membrane

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The majority of antibodies that target gp120 don’t neutralize HIV

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The majority of antibodies that target gp120 don’t neutralize HIV

CD4 Binding

Sitemiércoles 4 de abril de 12

The majority of antibodies that target gp120 don’t neutralize HIV

Glycosylation

CD4 Binding

Sitemiércoles 4 de abril de 12

The majority of antibodies that target gp120 don’t neutralize HIV

Glycosylation

Variable Loops

CD4 Binding

Sitemiércoles 4 de abril de 12

Heavychain

Light chainLight chain

Heavychain

Antibodies are multi-domain proteins secreted by B cells

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Antibodies are multi-domain proteins secreted by B cells

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VL

VH

VL

VH

Antibodies are multi-domain proteins secreted by B cells

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VL

VH

VL

VH

CH CH

CL

CL

Antibodies are multi-domain proteins secreted by B cells

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VL

VH

VL

VH

CH CH

CL

CL

Antibodies are multi-domain proteins secreted by B cells

antigenbinding sites

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Antibody-encoding genes get randomly rearranged in B cells to increase diversity

Germ Line DNASame

for all cells

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Antibody-encoding genes get randomly rearranged in B cells to increase diversity

Variable Constant

Germ Line DNASame

for all cells

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Antibody-encoding genes get randomly rearranged in B cells to increase diversity

Variable Constant

Germ Line DNASame

for all cells

Rearranged DNAUnique to each B cell (allele)

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Antibody-encoding genes get randomly rearranged in B cells to increase diversity

Variable Constant

Germ Line DNASame

for all cells

mRNA2,644,240 potential

combinations

Rearranged DNAUnique to each B cell (allele)

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B cells undergo fast naturalselection, which further increases diversity

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B cells undergo fast naturalselection, which further increases diversity

B cellsproliferate with

high mutation rate

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B cells undergo fast naturalselection, which further increases diversity

B cellsproliferate with

high mutation rate

Follicular Dendritic Cells

select forbinding affinity

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Effective antibodies differ on sequence but share similar structures

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Effective antibodies differ on sequence but share similar structures

VLightVHeavy

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Effective antibodies differ on sequence but share similar structures

VLightVHeavy

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Effective antibodies differ on sequence but share similar structures

VLightVHeavy

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Effective antibodies differ on sequence but share similar structures

Same germ line allele

VLightVHeavy

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Similar binding suggests convergent evolution

Paratope

SharedEpitope

Germ Line

Mature gp120

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Germ line divergence (%)

SequenceIdentity

withPG04 (%)

# Reads110K reads of HC

from a single donor

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Sequencing reveals that divergent antibodies are rare

Germ line divergence (%)

SequenceIdentity

withPG04 (%)

# Reads110K reads of HC

from a single donor

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Germ line divergence (%)

SequenceIdentity

withPG04 (%)

EffectiveNon-effective

Sequencing reveals that neutralizing antibodies are divergent

110K reads of HC from a single donor

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Germ line divergence (%)

SequenceIdentity

withPG04 (%)

110K reads of HC from a single donor

Sequencing reveals maturation lineages

Same CDR H3 Family

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Germ line divergence (%)

SequenceIdentity

withPG04 (%)

110K reads of HC from a single donor

Sequencing reveals maturation lineages

Same CDR H3 Family

GoodNeutralizer

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Cross-donor phylogenetic analysis can identify

neutralizing antibodies

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Cross-donor phylogenetic analysis can identify

neutralizing antibodies

High performing antibodies from other patients

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Cross-donor phylogenetic analysis can identify

neutralizing antibodies

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Cross-donor phylogenetic analysis can identify

neutralizing antibodies

56 mutations

41 mutations

23 mutations

93 mutations

VRC03High

Performing

gp140

germ line

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High performingintermediates

could form the basis of an

effective HIV vaccine

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