hiv-1 antibodies
TRANSCRIPT
nacho cabalLEro Presen
ted by
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miércoles 4 de abril de 12
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
miércoles 4 de abril de 12
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
miércoles 4 de abril de 12
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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