IAS 2014, Melbourne

1. Mechanisms of non-pathogenicity in HIV- Lessons from paediatric infection IAS 2014, Melbourne

2. Representative example of a paediatric ‘non-progressor’ PS-517-C dob Jan 2005 HLA A*30:02/68:02 B*15:10/42:01 C*03:03/17:01 PS-517-M HLA-A*30:02/30:04 B*42:01/58:02 C*06:02/17:01 No protective HLA alleles

3. CD4 count changes from birth in PS-517-C Uninfected children PS-517-C Absolute CD4 90th c 10th c 90th c CD4% 10th c

4. CD4 count changes from birth in PS-517-C Absolute CD4 CD4%

5. High CD4 counts in the setting of persistently high viral loads Uninfected children PS-517-C Absolute CD4 90th c 10th c 90th c CD4% 10th c

6. In HIV-infected children with normal CD4 counts viral loads decline over 5yrs to a ‘setpoint’ of 104-105

7. Normal CD4 countsin the setting of persistently high viral loads

8. Normal CD4 countsin the setting of persistently high viral loads Sooty Mangabeys African Greens • Attenuated immune activation • Avoid bystander damage • Preserve T cell populations • Protects from AIDS Adult viraemic non-progressors • Asymptomatic • Preserve T cell populations Silvestri et al, Immunity 2003 Bosinger et al, JCI 2009 Rotger et al, JCI 2011

9. Potential mechanism: Low immune activation despite persistent high viral loads

10. Potential mechanism: Low immune activation despite persistent high viral loads Representative CD4 data Lack of progression to AIDS = Attenuated immune activation

11. Immune activation: strongly correlated with CD4 count in ART-naïve paediatric infection Normal range for uninfected age-matched children Normal range for uninfected age-matched children p=0.004 p=0.002 n=25 n=25 n=44 n=44 n=28 n=28 n=19 n=19

12. No relationship between immune activation and viral load in paediatric infection r=0.11 p=ns

13. Defect in IL-2 production by CD4 cells in progressors versus non progressors Response to SEB; Muenchhoff et al unpublished

14. IL-2 response in CD4 cells in ART-naïve children is strongly correlated to CD4 count r=0.58 p<0.0001 Response to SEB; Muenchhoff et al unpublished

15. Low CCR5 expression on central memory CD4 cells correlates with high CD4 count in paediatric HIV Consistent with sooty mangabey and adult viraemic non progressors Paiardini et al, Nature Medicine 2012 Klatt et al, Plos Path 2014

16. PS-517-M is an adult viraemic non-progressor Viral load CD4 count Antenatal CD4

17. Mothers of paediatric non-progressors include a significant number of AVNPs Mothers of paediatric non-progressors 1000 Absolute CD4 r = -0.20 p = ns r = -0.57 p < 0.0001 500 Mothers of paediatric progressors 0 2 3 4 5 6 Log viral load Viral load

18. Paediatric ‘elites’ ‘Non-progressors’ (normal CD4) ‘Viral controllers’ (viral load <1000)

19. Paediatric ‘elites’ GOS-041-C 12yo CD4 1250/mm3 CD4% 42% VL<50

20. GOS-041-C 12yo CD4 1250/mm3 CD4% 42% VL<50 Paediatric ‘elites’ Positive GOS-041-C Negative

21. GOS-041-C 12yo CD4 1250/mm3 CD4% 42% VL<50 HLA-B*57:03 Adult elite controllers – enrichment of protective HLA alleles Paediatric ‘elites’ Positive GOS-041-C Negative

22. Distinct strategies to non-pathogenicity in paediatric infection ‘Non-progressor’ – high CD4/high viral load: sooty mangabey-type ‘Viral controller’ – high CD4/low viral load: Elite controller-type Conclusion

23. Acknowledgements Kimberley Hospital, South Africa Dr Pieter Jooste The University of Oxford Professor Philip Goulder Dr Paolo Paioni Dr Jacob Hurst Dr HenrikKloverpris Dr Max Muenchhoff Goulder Group Great Ormond Street Hospital, London UK Gareth Tudor-Williams, St Marys Hospital, London UK

24. Sooty Mangabey – Similar Phenotype to PSP? Bosinger et al JCI 2009