HIV-1 Antibodies

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CD4 gp120trimer

Helper T-cell

MembraneCCR40co-receptor

HIV-1 Membrane


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



CD4 Binding

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Glycosylation

CD4 Binding



Glycosylation

Variable Loops

CD4 Binding


Heavychain

Light chainLight chain

Heavychain

Antibodies are multi-domain proteins secreted by B cells




VL

VH

VL

VH



VL

VH

VL

VH

CH CH

CL

CL



VL

VH

VL

VH

CH CH

CL

CL


antigenbinding sites


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

Germ Line DNASame

for all cells



Variable Constant

Germ Line DNASame

for all cells



Variable Constant

Germ Line DNASame

for all cells

Rearranged DNAUnique to each B cell (allele)



Variable Constant

Germ Line DNASame

for all cells

mRNA2,644,240 potential

combinations

Rearranged DNAUnique to each B cell (allele)


B cells undergo fast naturalselection, which further increases diversity



B cellsproliferate with

high mutation rate



B cellsproliferate with

high mutation rate

Follicular Dendritic Cells

select forbinding affinity


Effective antibodies differ on sequence but share similar structures



VLightVHeavy



VLightVHeavy



VLightVHeavy



Same germ line allele

VLightVHeavy


Similar binding suggests convergent evolution

Paratope

SharedEpitope

Germ Line

Mature gp120


Germ line divergence (%)

SequenceIdentity

withPG04 (%)

# Reads110K reads of HC

from a single donor


Sequencing reveals that divergent antibodies are rare


SequenceIdentity

withPG04 (%)

# Reads110K reads of HC

from a single donor



SequenceIdentity

withPG04 (%)

EffectiveNon-effective

Sequencing reveals that neutralizing antibodies are divergent

110K reads of HC from a single donor



SequenceIdentity

withPG04 (%)


Sequencing reveals maturation lineages

Same CDR H3 Family



SequenceIdentity

withPG04 (%)


Sequencing reveals maturation lineages

Same CDR H3 Family

GoodNeutralizer


Cross-donor phylogenetic analysis can identify

neutralizing antibodies




High performing antibodies from other patients







56 mutations

41 mutations

23 mutations

93 mutations

VRC03High

Performing

gp140

germ line


High performingintermediates

could form the basis of an

effective HIV vaccine


Technology

HIV-1 Antibodies