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Novel Approaches : T reatment and HIV P athogenesis L. Trautmann, Ph.D. VGTI Florida

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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Novel Approaches : T reatment and HIV P athogenesis L. Trautmann, Ph.D. VGTI Florida

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  1. Novel Approaches: Treatment and HIV Pathogenesis L. Trautmann, Ph.D. VGTI Florida

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. HIV-Specific CD8 TCellsWanewithAntigenDecay

  10. 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

  11. ImprovedFunctionafterAntigenDecay High Ag Low Ag Low Ag High Ag Under low antigen load, HIV-specific CD8 T cells gain poly-functionality

  12. TCR Repertoire Changes withAntigenLevels ART ART

  13. IncreasedFunctionwithLowAntigenat the Clonal Level Low Ag High Ag ART The same clonotype gained function after decrease of antigen load

  14. 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

  15. 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

  16. HIV-Specific CD8 T Cells under ART HIV-specific CD8 T cells Increase the number of HIV-specific CD8 T cells

  17. 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

  18. 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

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