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Description : Neonatal and paediatric immunology relevant to HIV persistence.

Tags : Pediatrics, Child Health, pediatric practice, pediatrician, health providers, HIV-infected infants, Adolescent Transition, HIV-infected adolescents, paediatric immunology, Neonatal

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IAS 2016 Towards an HIV Cure Symposium Durban, South Africa www.iasociety.org Neonatal and paediatric immunology relevant to HIV persistence Deena Gibbons PhD Peter Gorer Department of Immunobiology Kings College London & Nigel Klein MD PhD Institute for Child Health University College London
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Neonatal Immunology and HIV Infant immunology qualitatively/ quantitatively different from that in the adult. Different immune response to HIV Different HIV susceptibility Different HIV persistence unique aspects towards cure. www.iasociety.org
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So what is different in infants? Innate immunity Monocytes DCs PMNs TLRs Levy et al, Blood 108:1284 (2006); Smed-Sorenson et al, J Virol 79:8861 (2005) Impaired response to TLR7 (detects ss RNA of HIV) in neonatal monocytes pDC: mDC in adult 1:2 pDC: mDC in infant 3:1 www.iasociety.org
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So what is different in infants? Adaptive immunity T follicular helper cells T cells B cells Development of TFH in newborn mice defective compared to adults -major reservoir of HIV T memory stem cell (TSCM)? -HIV reservoir Majority are naïve in infant (less susceptible to HIV?) Much higher CD4:CD8 ratio Banga et al, Nat Med 22:754 (2016); Bamford et al, Clin Exp Immunol 181:110 (2014) Debock et al, JI 191:1231 (2013); Buzon et al, Nat Med 20:139 (2014). www.iasociety.org
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Sundaravaradan et al PNAS 103: 11701 (2006) 3x increased replication of HIV in cord blood T cells 9x increased replication of HIV in cord blood monocytes Differential expression of host factors determine this susceptibility Contributes to faster disease progression in neonates Increased replication of HIV in CB mononuclear cells Sundaravaradan et al Virology 400:32 (2010) www.iasociety.org
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Although under optimal circumstances, lymphocytes from neonates can mount robust responses, the responses in neonates, particularly Th1 responses, are sub-optimal / almost non-existent, conventionally explained as a way to maintain tolerance. Birkholz et al, Human Immunology 75 584 (2014) www.iasociety.org Zaghouani and Adkins, Trends Immunol 30:.585 (2009). Neonatal T cell Function
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Infants do make immune responses to HIV Thobakgale et al, J Virol. 81:12775 (2007) www.iasociety.org
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Tolerogenic environment Decreased type 1 IFNs Decreased levels of Th1 cytokines (IL12/IFN), some bias towards Th2 and extracellular pathogen clearance Low magnitude (or non existent) CD4 and CD8 responses with narrow specificity Contributes to faster disease progression in neonates? Prendergast et al, Nat Rev Immunol 12:636 (2012) Lohman-Payne et al, Clin Exp Immunol178:86 (2014), Wang et al J. Leuk Biol 97:391 (2015) Does the T cell function influence HIV viraemia in children? www.iasociety.org
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Log10 HIV-1 RNA plotted against age in untreated HIV-infected children Log10 RNA copies/ml 0 2 4 6 8 Age in years 10 3 www.iasociety.org 4 5 6 PENTA, AIDS 12:F1-F8 (1998)
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But… neonatal CD4 are not inert.. just different Adult Baby IL-17 IFN …..they make CXCL8 www.iasociety.org CXCL8 CD4
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% of CD4 making CXCL8 decreases with age www.iasociety.org
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Mainly produced by epithelia, macrophages, fibroblasts Two forms 77aa/72aa .Recruits neutrophils to phagocytose antigen Human PMNs can’t respond to IL17 Binds CXCR1 & CXCR2 Levels of receptors are tightly controlled www.iasociety.org CXCL8
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CXCR1+ve CD8 defines a highly cytotoxic CD8 T cell Does CXCR1 define a “rapid-responder” subset of CD8 T cells that bridges the gap between the innate and acquired immune responses. Interestingly, significant expression of CXCR1 on HIV-1–specific CD8 T cells in individuals on HAART was restricted to persons who were able to control HIV-1 replication when taken off HAART. Takata et al. Blood 119:1390 (2012) Hess et al Blood 104:3463-3471 (2004) www.iasociety.org CXCL8 receptors
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Summary I www.iasociety.org Human neonatal immune system is not just an immature version of the adult Neonates have different responses - not sub-optimal. Classic adult HIV reservoirs may not be the same in infants
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Thymic Output is a key difference Vital for a diverse T-cell repertoire High thymopoesis in infancy, declining with age Difficult to measure / complex interplay Bains et al Blood 2009 Sangaard et al AIDS 28.209 2014 www.iasociety.org
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Increased Thymic output leads to a different pattern of Immune Reconstitution Sefe et al Paeds and Child Health 17:121. 2007 Pakker et al Nat Med 4.208. 1998 Bunupuradah et al AIDS 27:579 2013 www.iasociety.org
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The decline in Thymic Output has an important influence on eventual CD4 count www.iasociety.org
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The decline in Thymic Output has an important influence on eventual CD4 count Robbins et al CID 48.350 2009 Walker AS Manuscript in preparation from Arrow Trial www.iasociety.org
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age THYMUS EFFECTOR MEMORY T CELLS CD45RO+ NAÏVE T CELL POOL CD45RA+ antigen antigen death ✟ death ✟ death ✟ HIV Reservoirs may be different in children and can be influenced by the balance between tolerogenic environment and drivers of immune activation www.iasociety.org
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Cells more permissive to HIV infection are present in newborns and early childhood Bunders et al Immunobiology 120:4383 2012 Lawrie et al SAMJ 105:589 2015 Targets in Gut and LNs found in neonates More memory cells and activation in Africa www.iasociety.org
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Drivers of immune activation may exceed immune tolerance Doyle et al submitted Prendergast et al et al. AIDS Res. and Hum Retr. 28:465 (2012) Mold et al Science 322:1562 2008 www.iasociety.org
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Majority of infants treated early don’t seroconvert www.iasociety.org Payne et al Lancet ID 15:803 2015 Butler et al PIDJ 34:3 2015
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New initiatives to understand immunological responses associated with viral control time HIV RNA Birth/perinat al HIV infection On ART (acute phase) Off-ART (interruption/low adherence) 50 cp/mL slow suppressor rapid suppressor rapid rebounder slow rebounder EPPICC IMPAACT 1115 CHER CHERUB-UK NEVEREST CHANGES Thai Cohort www.iasociety.org IMPAACT 1115 CHER PENTA11 Elite controllers Palma P. et al. J. Viral Eradic 2015
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Summary II www.iasociety.org Children have much higher Thymic Output with better immune reconstitution Infants do not seroconvert to HIV if ART started early which affords unique opportunities for immune modulation to HIV The balance between immune tolerance and activation may be key to the future Cure agenda for children

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