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

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ias 2014 melbourne

Mechanisms of non-pathogenicity in HIV- Lessons from paediatric infection

IAS 2014, Melbourne

slide2

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

slide3

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

slide5

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

slide6

In HIV-infected children with normal CD4 counts

viral loads decline over 5yrs to a ‘setpoint’ of 104-105

slide8

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

slide10

Potential mechanism: Low immune activation despite persistent high viral loads

Representative

CD4 data

Lack of progression to AIDS = Attenuated immune activation

slide11

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

slide13

Defect in IL-2 production by CD4 cells in progressors versus non progressors

Response to SEB; Muenchhoff et al unpublished

slide14

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Response to SEB; Muenchhoff et al unpublished

slide15

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

slide16

PS-517-M is an adult viraemic non-progressor

Viral load

CD4 count

Antenatal CD4

slide17

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

slide18

Paediatric ‘elites’

‘Non-progressors’ (normal CD4)

‘Viral controllers’ (viral load <1000)

slide19

Paediatric ‘elites’

GOS-041-C 12yo

CD4 1250/mm3 CD4% 42% VL<50

slide20

GOS-041-C 12yo

CD4 1250/mm3 CD4% 42% VL<50

Paediatric ‘elites’

Positive

GOS-041-C

Negative

slide21

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

slide22

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

slide23

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