Role of V3 Region in HIV Entry to CD4 T-Cells
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Huang, C. C., Tang, M., Zhang, M. Y., Majeed, S., Montabana,
E., Stanfield, R. L., Dimitrov, D. S., Korber, B., Sodroski, J.,
Wilson, I. A., Wyatt, R., & Kwong, P. D.
(2005)
Sci
, 310(5750), 1025-1028
Journal Club Presentation
Chloe Jones,
Isabel Gonzaga, and
Nicole Anguiano
BIOL398: Bioinformatics Laboratory
October 15, 2014
O
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V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
O
u
t
l
i
n
e
●
V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
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HIV envelope has trimeric spike
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Contains 3 gp120 exterior 3 gp41 transmembrane
glycoproteins
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Host CD4 T-Cells bind to gp120 and causes
conformational change
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CD4 binds to coreceptor (CCR5 or CXCR4)
○
Virus enters CD4 T Cell
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Previous studies do not include V3 analysis in gp120
core structure in coreceptor binding site
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V3 plays many roles in coreceptor binding
o
Determines which coreceptor binds (CXCR4 or
CCR5)
o
Immune responses against HIV targeted towards V3
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3 Clade B isolates of gp120
core were expressed,
deglycosylated, purified and
complexed with CD4 + fab X5
antibody
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Overall, components maintain
individual structures
○
Large difference in X5: 17Å
induced fit
O
u
t
l
i
n
e
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V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
V3 structure facilitates binding to and interaction with co-receptors
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
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Uppercase: conserved
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Lowercase: variable
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Yellow: Arg-Pro motif
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Green: Gly-Pro-Gly-Arg
motif
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11th or 25th residue:
o
positive: CXCR4
o
uncharged/negative: CCR5
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CCR5 sequences more conserved
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Electron Density
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Grey areas
B values (Atomic Mobility)
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Blue: Low
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Red: High
O
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t
l
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n
e
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V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
V3 structure facilitates binding to and interaction with coreceptors
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
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Salmon: Carbon
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Red: Oxygen
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Dark Blue: Nitrogen
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Orange: Disulfide
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V3 consists of fixed base,
accordion-like stem, a
nd β-
hairpin
tip
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Yellow: Arg-Pro Motif
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Orange: Cys-Cys Disulfide
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Conserved Arg-Pro motif
interrupts bonding in the sheet
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β-sheet interactions on the
returning strand resume at
residue 270 and continue to the
Cys-Cys Disulfide
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Green: Conserved Gly-Pro-
Gly-Arg β turn
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Tip has antiparallel β-sheet
structure with conserved β-
turn
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Returning strand is less
defined
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Proposed schematic of V3-
Coreceptor interaction
shows coreceptor N-
terminus binding to the V3
base and the V3 tip binding
to the second extracellular
loop
O
u
t
l
i
n
e
●
V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
V3 structure facilitates binding to and interaction with co-receptors
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
S
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p
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Monoclonal
antibodies 50.1, 58.2,
59.1, 83.1, and 447-
52D bind to
conserved V3 tip
blocking coreceptor
binding
O
u
t
l
i
n
e
●
V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
V3 structure facilitates binding to and interaction with co-receptors
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
A
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Two different views of the
accessibility
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Antibodies bind to either the
core or V3
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V3 engulfed in neutralizing
antibodies, proposing a role in
immunization.
O
u
t
l
i
n
e
●
V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
V3 structure facilitates binding to and interaction with co-receptors
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
S
t
r
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c
t
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r
e
o
f
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N
e
u
t
r
a
l
i
z
a
t
i
o
n
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V3 plays a major role in the establishment of the HIV virus within the body
●
Coreceptor interaction and altering quaternary interactions of V3 can aid in
HIV avoiding immune system and HIV entry into the cells
○
Conformational Changes important for coreceptor binding (CCR5 or
CXCR4)
○
Spikes on envelope allows for binding of receptors and virus entry,
“molecular hook”
●
From studying the V3 structure, the HIV virus it can be further examined
and analyzed towards progression and neutralization
○
Neutralization targets V3 region
S
u
m
m
a
r
y
●
V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells
●
V3 sequences are conserved and determine coreceptor used for viral entry
●
Coreceptor binding to V3 is determined by V3’s three-part structure
●
Coreceptor binds to V3 base and V3 tip binds to the second extracellular
loop of the coreceptor
●
Superimposing antibodies on V3 structure with core blocks coreceptor
binding
●
Accessibility of antibodies to V3 aids in immunodominance
●
Studying the structure of V3 can aid in the understanding of the
neutralization and progression of HIV virus
A
c
k
n
o
w
l
e
d
g
e
m
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n
t
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Loyola Marymount University
Kam D. Dahlquist, Ph. D
C
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t
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t
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o
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Huang, C. C., Tang, M., Zhang, M. Y., Majeed, S., Montabana, E., Stanfield, R. L., Dimitrov, D. S.,
Korber, B., Sodroski, J., Wilson, I. A., Wyatt, R., & Kwong, P. D. (2005). Structure of a V3-containing
HIV-1 gp120 core. Science, 310(5750), 1025-1028. DOI: 10.1126/science.1118398
The V3 region of gp120 plays a crucial role in HIV entry to CD4 T-cells by determining the coreceptor usage. Studies focus on the structural aspects of V3, its conservation, coreceptor binding, and antibody accessibility. The HIV envelope structure, including trimeric spikes with gp120 and gp41 glycoproteins, facilitates viral entry into T-cells. The V3 region is essential for coreceptor binding site specificity and immune responses against HIV. Experimental data show the binding of V3 to the CD4 receptor in various HIV isolates. Understanding V3 structure aids in unraveling HIV neutralization mechanisms and disease progression.
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Presentation Transcript
Structure of V3-containing HIV-1 gp120 core Huang, C. C., Tang, M., Zhang, M. Y., Majeed, S., Montabana, E., Stanfield, R. L., Dimitrov, D. S., Korber, B., Sodroski, J., Wilson, I. A., Wyatt, R., & Kwong, P. D. (2005) Sci, 310(5750), 1025-1028 Journal Club Presentation Chloe Jones, Isabel Gonzaga, and Nicole Anguiano BIOL398: Bioinformatics Laboratory October 15, 2014
Outline V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
Outline V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
HIV Envelope Structure Allows for Viral Entry to T-Cells HIV envelope has trimeric spike Contains 3 gp120 exterior 3 gp41 transmembrane glycoproteins Host CD4 T-Cells bind to gp120 and causes conformational change CD4 binds to coreceptor (CCR5 or CXCR4) Virus enters CD4 T Cell
V3 Region Critical to Coreceptor Binding Site Previous studies do not include V3 analysis in gp120 core structure in coreceptor binding site V3 plays many roles in coreceptor binding o Determines which coreceptor binds (CXCR4 or CCR5) o Immune responses against HIV targeted towards V3
V3 of gp120 Core Binds to CD4 Receptor 3 Clade B isolates of gp120 core were expressed, deglycosylated, purified and complexed with CD4 + fab X5 antibody Overall, components maintain individual structures Large difference in X5: 17 induced fit
Outline V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry V3 structure facilitates binding to and interaction with co-receptors Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
V3 Sequence Conservation Determines Binding Coreceptor 11th or 25th residue: o positive: CXCR4 o uncharged/negative: CCR5 CCR5 sequences more conserved Uppercase: conserved Lowercase: variable Yellow: Arg-Pro motif Green: Gly-Pro-Gly-Arg motif
Electron Density and B Values Vary Along V3 Electron Density Grey areas B values (Atomic Mobility) Blue: Low Red: High
Outline V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry V3 structure facilitates binding to and interaction with coreceptors Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
V3 has a three-part structure Salmon: Carbon Red: Oxygen Dark Blue: Nitrogen Orange: Disulfide V3 consists of fixed base, accordion-like stem, and - hairpin tip
V3 Base consists of two anti-parallel beta sheets Yellow: Arg-Pro Motif Orange: Cys-Cys Disulfide Conserved Arg-Pro motif interrupts bonding in the sheet -sheet interactions on the returning strand resume at residue 270 and continue to the Cys-Cys Disulfide
V3 has a highly conserved tip Green: Conserved Gly-Pro- Gly-Arg turn Tip has antiparallel -sheet structure with conserved - turn Returning strand is less defined
V3 points downwards towards the target cell when bound to CD4
Co-receptor binds to V3 base and V3 tip binds to extracellular loops Proposed schematic of V3- Coreceptor interaction shows coreceptor N- terminus binding to the V3 base and the V3 tip binding to the second extracellular loop
Outline V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry V3 structure facilitates binding to and interaction with co-receptors Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
Superimposing antibodies on V3 structure with core blocks coreceptor binding Monoclonal antibodies 50.1, 58.2, 59.1, 83.1, and 447- 52D bind to conserved V3 tip blocking coreceptor binding
Outline V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry V3 structure facilitates binding to and interaction with co-receptors Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
Accessibility of Antibodies to V3 Aids In Immunodominance Two different views of the accessibility Antibodies bind to either the core or V3 V3 engulfed in neutralizing antibodies, proposing a role in immunization.
Outline V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry V3 structure facilitates binding to and interaction with co-receptors Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
Structure of V3 Gives Insight About Progression and Neutralization V3 plays a major role in the establishment of the HIV virus within the body Coreceptor interaction and altering quaternary interactions of V3 can aid in HIV avoiding immune system and HIV entry into the cells Conformational Changes important for coreceptor binding (CCR5 or CXCR4) Spikes on envelope allows for binding of receptors and virus entry, molecular hook From studying the V3 structure, the HIV virus it can be further examined and analyzed towards progression and neutralization Neutralization targets V3 region
Summary V3 region of gp120 protein plays a critical role in HIV entry to CD4 T-Cells V3 sequences are conserved and determine coreceptor used for viral entry Coreceptor binding to V3 is determined by V3 s three-part structure Coreceptor binds to V3 base and V3 tip binds to the second extracellular loop of the coreceptor Superimposing antibodies on V3 structure with core blocks coreceptor binding Accessibility of antibodies to V3 aids in immunodominance Studying the structure of V3 can aid in the understanding of the neutralization and progression of HIV virus
Acknowledgements Loyola Marymount University Kam D. Dahlquist, Ph. D
Citation Huang, C. C., Tang, M., Zhang, M. Y., Majeed, S., Montabana, E., Stanfield, R. L., Dimitrov, D. S., Korber, B., Sodroski, J., Wilson, I. A., Wyatt, R., & Kwong, P. D. (2005). Structure of a V3-containing HIV-1 gp120 core. Science, 310(5750), 1025-1028. DOI: 10.1126/science.1118398
