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Arne Schneidewind Partners AIDS Research Center Boston

Arne Schneidewind Partners AIDS Research Center Boston

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Arne Schneidewind Partners AIDS Research Center Boston

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  1. Selection of CTL escape mutations is determined by both the ability to avoid CTL recognition and by minimizing the impact on viral replicative capacity Arne Schneidewind Partners AIDS Research Center Boston

  2. HLA-B27

  3. HLA-B27 restricted Epitope KK10

  4. L268M is an early, partial escape mutation

  5. R264K is the dominant escape mutation

  6. R264K L268M S173A R264K is accompanied by S173A

  7. Replicative capacities of KK10-variants

  8. Replicative capacities of KK10-variants

  9. No reduction in RC for L268M

  10. R264K dramatically reduces RC

  11. S173A restores RC of R264K

  12. Replicative capacities of KK10-variants

  13. Replicative capacities of KK10-variants Impact on replicative capacity and requirement for compensation delays escape in B27-KK10

  14. Replicative capacities of KK10-variants Are there alternative ways to escape the CTL pressure against KK10?

  15. R264T Alternative Escape Mutations in KK10

  16. Alternative Escape Mutations in KK10

  17. Escape Mutations in KK10 abrogate binding to HLA-B27

  18. Alternative Escape Mutations in KK10 Replication capacity of SARKLM > than replication capacity of alternative escape mutants

  19. Simulation of CTL pressure

  20. Simulation of CTL pressure

  21. Simulation of CTL pressure ------------------------- -------- -----------------

  22. In Vitro Replication Capacity In Vivo Replication Capacity Virus HLA Binding Replication (WT) KRWIIL/MGLNK strong Replication (R264K) KKWIIL/MGLNK weak Replication (R264T/Q/G) KTWIIL/MGLNK KQWIIL/MGLNK KGWIILGLNK very weak Replication (SARKLM) KKWIIMGLNK + S173A weak Time Time Conclusions

  23. Conclusions • All CTL escape mutations at position P2 of KK10 efficiently abrogate binding to HLA-B27. • Replicative capacity of the frequent R264K escape mutation is dramatically reduced. • S173A efficiently compensates for the R264K replicative defect.

  24. Conclusions • The compensated R264K mutant (including S173A) replicated more efficiently than alternative escape mutations in the presence of KK10-specific CTL pressure. • Replication capacities in vitro correlate well to the frequency of escape mutations in vivo. • An in vivo threshold determines the propensity for escape variants to be selected.

  25. Acknowledgements Partners AIDS Research Center:California State University, San Marcos: Mark A. Brockman Bianca R. Mothé Yaoyu E. Wang Huabiao Chen Todd J. Suscovich La Jolla Institute for Allergy and Immunity: Bin Li Rahma I. Adam John Sidney Rachel L. Allgaier Alessandro Sette Thomas Kuntzen Cesar Oniangue-Ndza Christian Brander Funding: Bruce D. Walker Todd M. Allen R01-AI054178 + R21-AI067078