HIV/AIDS at 30: Back to the Future BHIVA / Wellcome Trust Multidisciplinary Event to mark World AIDS Day 2011 British HIV Association (BHIVA) 2011 HIV/AIDS at 30: Back to the Future BHIVA / Wellcome Trust Multidisciplinary Event to mark World AIDS Day 2011 Professor Jonathan Weber Imperial College London Thursday 1 December 2011, Wellcome Collection Conference Centre, London 1
The Holy Grail: where is the cure? Jonathan Weber Imperial College London Dante Gabriel Rossetti The Berlin patient...a cure is possible.but this price is too high N Engl J Med, 2009; 360:692 2
Rapid rebound in virus when ART stopped HIV RNA 50 CD4 count 0 1 Years on ART off ART HIV DNA in infected cells is always detectable HIV RNA HIV DNA CD4 count 50 0 1 Years on ART Chun et al., Nature 1997; 387:183; Finzi et al., Science 1997; 278:1295; Wong et al., Science 1997; 278:1291 3
No such thing as an undetectable viral load HIV RNA 50 HIV DNA CD4 count 1 0 1 Years on ART Palmer et al., Proc Natl Acad Sci U S A. 2008;105:3879-84 Maldarelli et al., Plos Pathogens 2007; 3:484 Two primary barriers: Cellassociated viral DNA Persistent viraemia on ART 4
Identifying the source of HIV viraemia on ART is essential to eradication Active replication cycles Stable reservoirs Infected cell X Uninfected cell HIV production can be completely blocked by ART IMPROVED ART NEEDED HIV production from reservoirs is NOT blocked by ART NEW STRATEGIES NEEDED Treatment intensification leads to no change in viremia or HIV DNA. HIV RNA HIV DNA HAART PLUS T20 or LPV/r or ATV/r or raltegravir CD4 count 50 1 0 1 Years on ART intensification Dinoso et al., Proc Natl Acad Sci U S A, 2009. 106(23): p. 9403-8; McMahon et al., Clin Infect Dis, 2010. 50(6): 912-9; Ghandi et al., J Infect Dis. 2010 Jan 15;201(2):293-6 ; Buzon et al., Nat Med, 2010 16: 460 5
Reservoir reduced with early treatment Log HIV DNA copies / million cells ADN VIH-1 (Log copies/million de PBMC) Chronic infection (n=135) Acute infection (n=22) Time on ART (years) Hocqueloux et al., 16 th CROI, Montreal, 2009; abstract #515; Hocqueloux et al., AIDS 2010; 24:1598 Population Genetics of Ongoing Replication NO Ongoing Replication Ongoing Replication Divergence Pretherapy During therapy Divergence 6
Similar Genetic Diversity and Population Structure Before and After Initiation of Antiretroviral Therapy HIV-1 RNA (copies/ml) 10 7 10 6 10 5 10 4 10 3 10 2 10 1 D4T/3TC/EFV 1 0 0 50 100 150 200 250 300 Time on Study (days) 1000 900 800 700 600 500 400 300 200 100 CD4 (cells/µl) 1019.510 1030.723 1019.522 145242-12 1019.516 1019.57 1206.97 1115.81 1115.89 1115.810 145241-9 1206.95 145242-3 145241-10 145241-14 1115.816 1115.83 145241-13 1206.914 1115.820 1206.98 145242-1 1030.71 1115.814 1019.52 1019.517 1030.716 No evidence of ongoing viral evolution during ART suppression 0.001 substitutions/site Analysis of viraemia after prolonged suppression HIV in cellular DNA HIV in plasma HIV in resting CD4 Predominant Plasma Clone Repeated isolation Identical sequence NOT present in resting CD4+ cells NOT a major constituent of cellular proviral DNA Bailey et al., 2006 7
Residual viraemia Low grade viraemia exists in most patients Not suppressed by ART intensification This viraemia does not evolve At least in peripheral blood compartment Observations consistent with reactivation from latently infected cells Anatomical or cellular origin unclear gut lymphoid tissue (GALT)? Two primary barriers: Cellassociated viral DNA Persistent viraemia on ART 8
Bone marrow Latent infection can be established in many T cells Thymus Peripheral circulation Ag M M M M Naive Effector/ transitional Central memory Multipotent progenitor cells Naïve T cells Transitional memory Central memory Latent reservoir Chun et al., Nature 1997; 387:183; Finzi et al., Science 1997; 278:1295; Brooks et al., Nat Med 2001; 7:459 ; Chomont et al., Nat Med 2009; 15: 893; Dai et al., J Virol 2009: 83(9):4528-37; Carter et al., Nat Med 2010; 16: 446; Wightman et al., J Infect Dis 2010 (in press) T cell phenotype associates with proviral DNA Chomont 2009 Nat Med 9
GI tract is the major viral reservoir on ART HIV DNA Copies per million cells Chun et al., J Infect Dis 2008 Yukl et al., J Infect Dis 2010 How to achieve a cure? 1. Suppress viraemia better: But how? Immunotherapy?? 2. Target latently infected cells: Activate the proviral reservoir exhaust histone deacetylase inhibitors Silence the proviral reservoir suppress epigenetic modification Target latently infected cells kill identify marker; HERVs? 3. Genetic modification delta32: protect 4. Do no harm 10
CHERUB Collaborative HIV Eradication of Reservoirs: UK BRC Scientific secretary: Dr John Frater (Oxon) HIV/AIDS at 30: Back to the Future BHIVA / Wellcome Trust Multidisciplinary Event to mark World AIDS Day 2011 British HIV Association (BHIVA) 2011 11