cd4 mimetics sensitize hiv -1-infected cells to adcc · • adcc response represents one of the...
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IAS 2015 Towards an HIV Cure symposium Vancouver
CD4 Mimetics Sensitize HIV-1-Infected Cells to ADCC
Andrés Finzi
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Antibody-dependent cellular cytotoxicity
• ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells
• Analysis of the correlates of protection in the RV144 vaccine trial suggested that increased
ADCC activity was linked with decreased HIV-1 acquisition (Haynes et al., 2012)
• Abs with potent ADCC activity were isolated from some RV144 vaccinees (Bonsignori et al., 2012)
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Exposure of ADCC-mediating Env epitopes
• Interaction of HIV-1 envelope (Env) with the CD4 receptor can occur within the same HIV-1-infected cell and is required for efficient exposure of ADCC-mediating Env epitopes (Veillette et al., 2014, Veillette et al, 2015)
The ability of Env to reach the CD4-bound conformation was found to be critical for exposure
of Env ADCC-mediating epitopes (Veillette et al., 2014, Richard et al., 2014, Veillette et al., 2015)
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HIV-1 reduces exposure of Env ADCC-mediating epitopes
Nef-Vpu- wt
Veillette et al., 2015
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Hypothesis
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Small CD4-mimetic compounds
CD4 CD4-mimetic compounds
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CD4-mimetics enhance recognition of HIV-1-infected primary CD4 T cells
DMSO JP-III-48 DMJ-I-228 sCD4
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CD4-mimetics enhance recognition of primary T cells infected with HIV-1 primary
isolates
HIV+ sera binding
Mock CH77 T/F CH77 6 Mo CH58 T/F CH58 6 Mo
DMSO
JP-III-48
DMJ-I-228
sCD4
M48U1
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CD4-mimetics enhance recognition and killing of primary T cells infected with HIV-1 primary isolates
JP-III-48 DMJ-I-228 sCD4 M48U1
Surface binding ADCC
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CD4-mimetics enhance recognition and killing of primary T cells infected with HIV-1 primary isolates
JP-III-48 DMJ-I-228 sCD4 M48U1
ADCC Surface binding
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CD4-mimetics enhance recognition and killing of primary T cells infected with HIV-1 primary isolates
JP-III-48 DMJ-I-228 sCD4 M48U1
ADCC Surface binding
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CD4-mimetics enhance recognition and killing of primary T cells infected with HIV-1 primary isolates
JP-III-48 DMJ-I-228 sCD4 M48U1
ADCC Surface binding
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JP-III-48 sensitizes primary CD4 T cells infected with transmitted/founder virus to
ADCC
JP-III-48 DMSO JP-III-48 DMSO
JP-III-48 DMSO JP-III-48 DMSO
JP-III-48 DMSO JP-III-48 DMSO JP-III-48 DMSO
JP-III-48 DMSO
JP-III-48 DMSO
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JP-III-48 sensitizes ex-vivo-expanded endogenously-infected primary CD4 T cells to ADCC
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JP-III-48 sensitizes ex-vivo-expanded endogenously-infected primary CD4 T cells to ADCC
Recognition by HIV+ sera
ADCC
DMSO JP-III-48
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Conclusions
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Conclusions
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Conclusions
See poster TULBPE03 on Tuesday for more details
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Acknowledgments
Dana-Farber Cancer Institute Joseph Sodroski
Navid Madani
University of Pennsylvania Beatrice Hahn
Amos B. Smith, III
Duke University Barton Haynes Sallie Permar
CEA-iBiTec-S Loïc Martin
CRCHUM Michel Roger
Daniel Kaufmann
FRSQ SIDA-MI network Volunteers Mario Legault
McGill Jean-Pierre Routy
University of Maryland Marzena Pazgier
Johns Hopkins University Arne Schön
Ernesto Freire
Finzi Lab Nirmin Alsahafi Mathieu Coutu
Jean-Philippe Chapleau Jonathan Richard
Shilei Ding Maxime Veillette Daria Zoubchenok
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CD4-mimetics enhance recognition of HIV-1-infected T cells
DMSO
sCD4
DMJ-I-228
JP-III-48
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CD4-mimetics enhance recognition of HIV-1-infected T cells
DMSO
sCD4
DMJ-I-228
JP-III-48
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CD4-mimetics enhance recognition of HIV-1-infected T cells
DMSO
sCD4
DMJ-I-228
JP-III-48
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CD4-mimetics enhance recognition of HIV-1-infected T cells
DMSO
sCD4
DMJ-I-228
JP-III-48
Vpu- Nef- Vpu-
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(Richard et al., PNAS 2015)
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(Richard et al., PNAS 2015)
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(Richard et al., PNAS 2015)
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TF #1 6-mo #1 TF #2 6-mo #2
TF #1 6-mo #1 TF #2 6-mo #2
TF #1 6-mo #1 TF #2 6-mo #2
Primary HIV-1 strains
Env
(Richard et al., PNAS 2015)
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ex-vivo-expanded endogenously-infected primary CD4 T cells
Env CD4 BST2
p24- p24+
(Richard et al., PNAS 2015)
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Env/CD4 interaction is required for efficient elimination of HIV-1-infected cells by ADCC