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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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Page 1: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

IAS 2015 Towards an HIV Cure symposium Vancouver

CD4 Mimetics Sensitize HIV-1-Infected Cells to ADCC

Andrés Finzi

Page 2: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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)

Page 3: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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)

Page 4: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

HIV-1 reduces exposure of Env ADCC-mediating epitopes

Nef-Vpu- wt

Veillette et al., 2015

Page 5: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

Hypothesis

Page 6: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

Small CD4-mimetic compounds

CD4 CD4-mimetic compounds

Page 7: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

CD4-mimetics enhance recognition of HIV-1-infected primary CD4 T cells

DMSO JP-III-48 DMJ-I-228 sCD4

Page 8: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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

Page 9: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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

Page 10: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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

Page 11: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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

Page 12: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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

Page 13: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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

Page 14: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

JP-III-48 sensitizes ex-vivo-expanded endogenously-infected primary CD4 T cells to ADCC

Page 15: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

JP-III-48 sensitizes ex-vivo-expanded endogenously-infected primary CD4 T cells to ADCC

Recognition by HIV+ sera

ADCC

DMSO JP-III-48

Page 16: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

Conclusions

Page 17: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

Conclusions

Page 18: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

Conclusions

See poster TULBPE03 on Tuesday for more details

Page 19: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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

Page 20: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

CD4-mimetics enhance recognition of HIV-1-infected T cells

DMSO

sCD4

DMJ-I-228

JP-III-48

Page 21: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

CD4-mimetics enhance recognition of HIV-1-infected T cells

DMSO

sCD4

DMJ-I-228

JP-III-48

Page 22: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

CD4-mimetics enhance recognition of HIV-1-infected T cells

DMSO

sCD4

DMJ-I-228

JP-III-48

Page 23: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

CD4-mimetics enhance recognition of HIV-1-infected T cells

DMSO

sCD4

DMJ-I-228

JP-III-48

Vpu- Nef- Vpu-

Page 24: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

(Richard et al., PNAS 2015)

Page 25: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

(Richard et al., PNAS 2015)

Page 26: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

(Richard et al., PNAS 2015)

Page 27: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

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)

Page 28: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

ex-vivo-expanded endogenously-infected primary CD4 T cells

Env CD4 BST2

p24- p24+

(Richard et al., PNAS 2015)

Page 29: CD4 Mimetics Sensitize HIV -1-Infected Cells to ADCC · • ADCC response represents one of the effector mechanisms used by the immune system to eliminate virally infected cells •

Env/CD4 interaction is required for efficient elimination of HIV-1-infected cells by ADCC


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