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Novel Approaches : T reatment and HIV P athogenesis L. Trautmann, Ph.D. VGTI Florida PowerPoint Presentation
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Novel Approaches : T reatment and HIV P athogenesis L. Trautmann, Ph.D. VGTI Florida. Beyond Anti-Retroviral T herapy. Antibodies, cytokines, gene therapy, chemotherapy. ART reduces HIV viremia to undetectable levels and increases life expectancy, but...

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slide1

Novel Approaches:

Treatment and HIV Pathogenesis

L. Trautmann, Ph.D.

VGTI Florida

slide2

BeyondAnti-RetroviralTherapy

Antibodies, cytokines, gene therapy, chemotherapy

  • ART reduces HIV viremia to undetectable levels and increases life expectancy, but...
    • immune activation does not normalize under ART
    • a small pool of latently infected cells persists under ART
    • low levels of residual viral replication can persist during ART
  • New strategies are being developed to:
    • decrease inflammation under ART
    • purge HIV latent reservoir under ART
    • achieve a natural control of viral replication without ART

Cell-based immunotherapies and therapeutic vaccines

slide3

In Vivo and In Vitro Models of Intervention under ART

New regimen of drugs in non-human primates to control viral load

New in vitro models of viral reactivation and inhibition of viral replication

slide4

HIV-Specific CD8 T CellscanEliminateReactivatedReservoirCells

Stimulation of HIV-1-Specific Cytolytic

T Lymphocytes Facilitates Elimination

of Latent Viral Reservoir after Virus Reactivation

Shan et al. Immunity 2012, 36(3): 491-501

slide5

Enhance T Cell Immunity Against HIV-1

VACCINE

ADJUVANT

Protein

DNA

Viral

vector

DC

High affinity

Cross-reactivity

High breadth

Co-stimulation

TCR

High

Proliferative

Capacity

CD8 /CD4

T cell

Mucosal Homing

High Cytotoxicity

Poly-functionality

TEMRA

High Frequency of Effector Memory

Long-lasting Central Memory

T EM

T CM

slide6

HIV-Specific CD8 T Cells Fate Depends on Antigen Load

HIV-specific CD8 T cells decrease to low levels after ART initiation

High levels of circulating viruses and HIV-specific CD8 T cells

When antiretroviral drugs suppress HIVto undetectable levels, HIV-specific CD8 T cells wane

START

ART

Circulating virus

HIV-specific CD8 T cells

Limit of detection

Time

slide7

HIV-Specific CD8 T Cells do not Control Viral Rebound

Viral load reaches pre-ART level after ART cessation and

is not controlled by the memory HIV-specific CD8 T cells

The virus rebounds after cessation of therapy as well as HIV-specific CD8 T cells

STOP

ART

Circulating virus

HIV-specific CD8 T cells

Limit of detection

Time

slide8

Analyzing HIV-Specific CD8 T Cells under ART

CD8 T cells express different T cell receptors (TCRs)

HIV-specific CD8 T cells can be detected using Tetramersof MHC I + HIV peptides recognizing the TCRs specific for these HIV peptides

The TCR repertoire is the ensemble of T cell clones called clonotypes expressing different TCRs recognizing a specific antigen

Each clonotypeexpresses a TCR encoded by a unique nucleotide sequence that can be used to track HIV-specific clonotypesin vivo

slide10

Phenotypic Changes afterAntigenDecay

Under low antigen load, HIV-specific CD8 T cells gain a more differentiated phenotype, express higher levels of IL7R and lower levels of negative regulator PD-1

slide11

ImprovedFunctionafterAntigenDecay

High Ag

Low Ag

Low Ag

High Ag

Under low antigen load, HIV-specific CD8 T cells gain poly-functionality

slide13

IncreasedFunctionwithLowAntigenat the Clonal Level

Low Ag

High Ag

ART

The same clonotype gained function after decrease of antigen load

slide14

Selection of Clonotypes with Superior Functional Capabilities

Tetramer

Only the clonotype becoming dominant under ART gained function under low antigen load compared to the total epitope-specific CD8 T cells

TRBV 6-2

1m

17m

1m

17m

ART

Low Ag

High Ag

Low Ag

High Ag

slide15

Selection of Clonotypes with Superior Functional Capabilities

HIV-specific CD8 T cells secreting cytokines upon restimulation before antigen decrease consisted only in the clonotype that became dominant under low antigen load

slide16

HIV-Specific CD8 T Cells under ART

HIV-specific

CD8 T cells

Increase the number of HIV-specific CD8 T cells

slide17

CD8 T Cells in Novel Approaches

Efficient CD8 T cells

at ART cessation

High number of CD8 T cells under ART

Control latent viral reservoir

Control viral rebound after ART withdrawal

Achieve functional cure

Drug free remission

Defining strategies to increase the number of high affinity HIV-specific CD8 T cells would help in controlling viral reservoirs under ART and in controlling viral rebound after ART cessation

slide18

Acknowledgements

VRC NIH

Daniel C. Douek

David A. Price

Richard A. Koup

TediE. Asher

David R. Ambrozak

Phillip Scheinberg

VGTI Florida

Rafick-Pierre Sékaly

Elias Haddad

Nicolas Chomont

Glenda Canderan

AbdelaliFilali-Mouhim

Montreal University

LouryJanbazian

McGill University

MohamadRachidBoulassel

Jean-Pierre Routy

FRSQ-SIDAMI

TRANSLATING RESEARCH INTO HEALTH