The HIV Cure Agenda CHIVA Oct 2016 Nigel Klein Institute of Child Health and Great Ormond Street Hospital, London, UK
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How frequently is HIV cured?
The Berlin patient
Restriction of HIV entry CD4 is the primary HIV-1 receptor Also requires co-receptor CCR5 (main co-receptor, early in infection) CXCR4 (develops later in infection) Dual tropic
Why is cure so difficult?
Barriers to Cure
naive and memory T cell pools THYMUS NAÏVE T CELL POOL CD45RA+ EFFECTOR MEMORY T CELLS CD45RO+ antigen antigen death death death age Total Number of T cells Remains Roughly Constant Throughout Adult Life
T Cell Activation and Proliferation DIVIDING CELLS THYMUS RESTING CELLS Activation ACTIVATED AND DIVIDING AND ACTIVATED DIVIDING AND DIVIDING CELLS CELLS CELLS return to resting state Death ACTIVATED CELLS Death Death
ART is very effective in reducing Immune Activation in children
Barriers to Cure
Barriers to Cure
Anatomical Reservoirs Lymphoid Tissue CNS GI Tract GU Tract
Barriers to Cure there are many
HIV-1 RNA (copies/ml) HIV-1 RNA (copies/ml) The Mississippi Baby 10 5 ART No ART 10 5 HIV RNA 19,812 copies/ml 10 4 10 3 Loss to follow up and stop ART at age 18 months 16,750 c/ml 10,564 c/ml 10 4 10 3 10 2 9 c/ml 10 1 0 10 20 30 40 50 Months of Life 10 2 HIV DNA+ 10 1 30 hours 3 days 10 days 20 days 30 days ART Persaud D, NEJM 2013 2014
Not a cure but has stimulated work in this area Viral reservoirs are important different in children
Visconti post treatment controllers
Low HIV DNA in Children who Achieve Viral Suppression by Age 1 Year Persaud D et al. JAMA Peds (in press)
Payne CROI 2015 Correlates with lower HIV proviral DNA: Cumulative duration of ART Cumulative continuous HIV-suppression
What about the future
Shock and Kill Strategy Barouch DH, Deeks SG, Science 2014
Examples of Strategies Currently in Human SHOCK Reactivating latentlyinfected cells Inhibit histone deacetylase Inhibit bromodomain extraterminal Activate toll-like receptors Activate protein kinase C Studies MINIMIZE RESERVOIR Limit reservoir with early treatment Antiretroviral therapy Broadly neutralizing antibodies Combination Cure KILL Viral clearance by the immune system Broadly neutralizing antibodies Therapeutic HIV vaccines Anti programmed cell death (PD)1 Anti PD ligand 1 HIV RESISTANT CELLS Transfusing cells without CCR5 gene Gene-editing therapy Bone marrow or cord blood transplantation
Gene therapy for HIV
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If treated early enough no antibody is generated
Majority of infants treated early don t seroconvert Payne et al Lancet ID 15:803 201 Butler et al PIDJ 34:3 2015
Long-term Treated Adolescents with No Detectable HIV ART at 15 days of life VL < 400 by 3 months of age VL suppression on ART for 15 years cart at 0.5 months VL < 400 at 3 months No detectable RNA DNA Replication competent virus HIV-specific immunity Immune activation Luzuriaga K, J Infect Dis 2014
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
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
The decline in Thymic Output has an important influence on eventual CD4 count
EPIICAL pla/ orm predic' ve)in)vitro)and)in)vivo) strategies) to) op' mise) the) management in#vitro#
SAMPLES FROM CHER COHORT SAMPLES FROM EUROPEAN COHORTS SCIENTISTS CONTAMINA TION BCR and TCR sequencing T and B-cells UCL UNIPD UNITOV - FACS analysis - Sorting B-cell CWRU RNA sequencing data analysis UM Fluidigm analysis RNA sequencing from 10 6 PBMC c-dna T-cell PBMC UKZN/AC - FACS analysis - Sorting www.iasociety.org
New initiatives to understand immunological responses associated with viral control HIV RNA On ART (acute phase) Off-ART (interruption/low adherence) 50 cp/ml slow suppressor rapid suppressor rapid rebounder slow rebounder Birth/perinat al HIV infection EPPICC IMPAACT 1115 CHER CHERUB-UK NEVEREST CHANGES Thai Cohort IMPAACT 1115 CHER PENTA11 Elite controllers time Palma P. et al. J. Viral Eradic 2015
The HIV Cure Agenda Its very busy It will be successful