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

2. 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 Representative example of a paediatric ‘non-progressor’

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

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

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

6. In HIV-infected children with normal CD4 counts viral loads decline over 5yrs to a ‘setpoint’ of 10 4 -10 5

7. Normal CD4 counts in the setting of persistently high viral loads

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

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

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

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

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

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 Response to SEB; Muenchhoff et al unpublished Defect in IL-2 production by CD4 cells in progressors versus non progressors

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 Response to SEB; Muenchhoff et al unpublished r=0.58 p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

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

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

17. Viral load Mothers of paediatric non- progressors Mothers of paediatric progressors r = -0.20 p = ns r = -0.57 p < 0.0001 1000 500 0 Absolute CD4 23456 Log viral load Mothers of paediatric non-progressors include a significant number of AVNPs

18. 1.‘Non-progressors’ (normal CD4) 1.‘Viral controllers’ (viral load <1000) Paediatric ‘elites’

19. GOS-041-C 12yo CD4 1250/mm 3 CD4% 42% VL<50 Paediatric ‘elites’

20. GOS-041-C 12yo CD4 1250/mm 3 CD4% 42% VL<50 Negative GOS-041-C Positive Paediatric ‘elites’

21. GOS-041-C 12yo CD4 1250/mm 3 CD4% 42% VL<50 HLA-B*57:03 Adult elite controllers – enrichment of protective HLA alleles Negative GOS-041-C Positive Paediatric ‘elites’

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. The University of Oxford Professor Philip Goulder Dr Paolo Paioni Dr Jacob Hurst Dr Henrik Kloverpris Dr Max Muenchhoff Goulder Group Kimberley Hospital, South Africa Dr Pieter Jooste Acknowledgements 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