IAS 2014, Melbourne

IAS 2014, Melbourne

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

PS-517-C dob Jan 2005HLA A*30:02/68:02 B*15:10/42:01 C*03:03/17:01

PS-517-MHLA-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’

90th c

10th c

90th c

10th c

Uninfected children PS-517-C

CD4%

Absolute CD4

CD4 count changes from birth in PS-517-C

CD4%

Absolute CD4

CD4 count changes from birth in PS-517-C

High CD4 counts in the setting of persistently high viral loads

90th c

10th c

90th c

10th c

Uninfected children PS-517-C

Absolute CD4

CD4%

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

Normal CD4 counts in the setting of persistently high viral loads

Sooty MangabeysAfrican Greens

Adult viraemic non-progressors

Silvestri et al, Immunity 2003Bosinger 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 damagePreserve T cell populations Protects from AIDS

AsymptomaticPreserve T cell populations

Potential mechanism: Low immune activation despite persistent high viral loads

Representative CD4 data

Potential mechanism: Low immune activation despite persistent high viral loads

Lack of progression to AIDS = Attenuated immune activation

Normal range for uninfected age-matched children

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

No relationship between immune activation and viral load in paediatric infection

r=0.11p=ns

Response to SEB; Muenchhoff et al unpublished

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

Response to SEB; Muenchhoff et al unpublished

r=0.58p<0.0001

IL-2 response in CD4 cells in ART-naïve children is strongly correlated to CD4 count

Consistent with sooty mangabey and adult viraemic non progressorsPaiardini 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

Viral loadCD4 count

Antenatal CD4

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

Viral load

Mothers of paediatric non-progressors

Mothers of paediatric progressors

r = -0.20p = nsr = -0.57

p < 0.0001

1000

500

0

Absolute CD4

2 3 4 5 6Log viral load

Mothers of paediatric non-progressors include a significant number of AVNPs

1. ‘Non-progressors’ (normal CD4)

2. ‘Viral controllers’ (viral load <1000)

Paediatric ‘elites’

GOS-041-C 12yoCD4 1250/mm3 CD4% 42% VL<50

Paediatric ‘elites’

GOS-041-C 12yoCD4 1250/mm3 CD4% 42% VL<50

Neg

ative

GO

S-04

1-C

Positi

ve

Paediatric ‘elites’

GOS-041-C 12yoCD4 1250/mm3 CD4% 42% VL<50

HLA-B*57:03

Adult elite controllers – enrichment of protective HLA alleles

Neg

ative

GO

S-04

1-C

Positi

ve

Paediatric ‘elites’

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

The University of Oxford

Professor Philip Goulder

Dr Paolo PaioniDr Jacob Hurst

Dr Henrik KloverprisDr 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

Sooty Mangabey – Similar Phenotype to PSP?

Bosinger et al JCI 2009