novel approaches: treatment and hiv pathogenesis l. trautmann, ph.d. vgti florida
TRANSCRIPT
Novel Approaches: Treatment and HIV Pathogenesis
L. Trautmann, Ph.D. VGTI Florida
Beyond Anti-Retroviral Therapy
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
Antibodies, cytokines, gene therapy, chemotherapy
Cell-based immunotherapies and therapeutic vaccines
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
HIV-Specific CD8 T Cells can Eliminate Reactivated Reservoir Cells
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
Enhance T Cell Immunity Against HIV-1
DCViral vector
ProteinDNA
ADJUVANT
High affinityCross-reactivityHigh breadth
High CytotoxicityPoly-functionality
High Proliferative
CapacityMucosal Homing
TEMRA High Frequency of Effector Memory Long-lasting Central Memory
VACCINE
TCRCo-stimulation
T CM
T EM
CD8 /CD4 T cell
HIV-Specific CD8 T Cells Fate Depends on Antigen Load
Limit of detection
Circ
ulati
ng v
irus
HIV
-spe
cific
CD
8 T
cells
Time
STARTART
When antiretroviral drugs suppress HIV to undetectable levels, HIV-specific CD8 T cells wane
High levels of circulating viruses and HIV-specific CD8 T cells
HIV-specific CD8 T cells decrease to low levels after ART initiation
HIV-Specific CD8 T Cells do not Control Viral Rebound
Limit of detection
Time
STOP
ART
The virus rebounds after cessation of therapy as well as HIV-specific CD8 T cells
Viral load reaches pre-ART level after ART cessation and is not controlled by the memory HIV-specific CD8 T cells
Circ
ulati
ng v
irus
HIV
-spe
cific
CD
8 T
cells
CD8 T cells express different T cell receptors (TCRs)
HIV-specific CD8 T cells can be detected using Tetramers of 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 clonotype expresses a TCR encoded by a unique nucleotide sequence that can be used to track HIV-specific clonotypes in vivo
Analyzing HIV-Specific CD8 T Cells under ART
HIV-Specific CD8 T Cells Wane with Antigen Decay
Phenotypic Changes after Antigen Decay
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
Improved Function after Antigen Decay
Low Ag Low Ag
Under low antigen load, HIV-specific CD8 T cells gain poly-functionality
High Ag High Ag
TCR Repertoire Changes with Antigen Levels
ART ART
Increased Function with Low Antigen at the Clonal Level
Low Ag
ART
The same clonotype gained function after decrease of antigen load
High Ag
Selection of Clonotypes with Superior Functional Capabilities
Tetramer
1m 17m
TRBV 6-2
1m 17mLow Ag Low Ag
ART
Only the clonotype becoming dominant under ART gained function under low antigen load compared to the total epitope-specific CD8 T cells
High Ag High Ag
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
HIV-Specific CD8 T Cells under ART
No ART ART
Quality - +++
Quantity +++ -
Increase the number of HIV-specific CD8 T cells
HIV
-spe
cific
CD
8 T
cells
CD8 T Cells in Novel Approaches
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
High number of CD8 T cells under ART
Control latent viral reservoir
Efficient CD8 T cells at ART cessation
Control viral rebound after ART withdrawal
Achieve functional cure Drug free remission
Acknowledgements
T R A N S L A T I N G R E S E A R C H I N T O H E A L T H
VGTI Florida Rafick-Pierre Sékaly Elias Haddad Nicolas ChomontGlenda CanderanAbdelali Filali-Mouhim
Montreal UniversityLoury Janbazian
McGill University Mohamad Rachid BoulasselJean-Pierre Routy
FRSQ-SIDAMI
VRC NIHDaniel C. DouekDavid A. PriceRichard A. KoupTedi E. AsherDavid R. AmbrozakPhillip Scheinberg