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Interactive Workshop “HIV Cure 101”: Challenges in identifying and

Interactive Workshop “HIV Cure 101”: Challenges in identifying and targeting the HIV reservoir Sarah Palmer Centre for Virus Research Westmead Millennium Institute for Medical Research University of Sydney. Definitions.

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Interactive Workshop “HIV Cure 101”: Challenges in identifying and

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  1. Interactive Workshop “HIV Cure 101”: Challenges in identifying and targeting the HIV reservoir Sarah Palmer Centre for Virus Research Westmead Millennium Institute for Medical Research University of Sydney

  2. Definitions Residual Viremia: Persistent HIV RNA measured in plasma at levels below the limit of detection of the standard clinical assay (20-50 copies/ml). Viral Reservoir: A viralreservoiris an anatomical site or cell type in which a replication-competent form of HIV persists, accumulating with more stable properties than the circulating pool of actively replicating virus. This HIV can persist even during effective therapy.

  3. Viremia Persists after Suppression by Antiretroviral Therapy Start Therapy (d4T/3TC/efavirenz) Start Therapy (d4T/3TC/efavirenz) 4 ± 2 c/ml 22 ± 6 c/ml bDNA bDNA <75 copies/ml Single-Copy Assay Single-Copy Assay < 1 copy/ml 107 107 106 106 105 105 104 104 Plasma HIV-1 RNA (copies/ml) 103 103 102 102 101 101 100 100 10-1 10-1 0 200 400 600 800 0 200 400 600 800 Time (days) Time (days) Palmer et al. JCM 2003 Maldarelli et al. PLoSPath 2007

  4. 720 study 720 study assay limit 11.6 copies/ml 1.5 copies/ml half-life= ∞ half-life=39 weeks Biphasic decline in persistent viremia over 7 years of treatment 100 32 10 3.2 1 0.32 Palmer et al. PNAS 2008

  5. Persistent HIV Infection The IAS Scientific Working Group on HIV Cure: Nature Reviews Immunology 2012 Palmer et al. JIM 2011

  6. Persistent HIV Infection

  7. CNS/CSF Measuring Persistent HIV • Where to Measure • Persistent Virus? • Peripheral Blood • Plasma • Cells: RNA versus DNA • Tissue Compartments • T cells • Other cell types • RNA versus DNA • Role of Replication • Defective HIV

  8. Measuring Persistent HIV Culture assay : IUPM Lewin & Rouzioux, AIDS 2011 Rouzioux & Richman, 2012

  9. Measuring Persistent HIV Infection

  10. CNS/CSF Persistent HIV Infection in Tissue

  11. Persistent HIV Infection in Tissues Svicher et al. Curr HIV/AIDs Rep. 2014

  12. Looking Ahead Does a “cure” require the total absence of HIV RNA and DNA? If not, then new more sensitive assays will be needed to differentiate between replication competent and non-replicating virus. Must all potential reservoirs be analyzed? If not, are we confident that certain reservoirs are determinative of cure/remission? With advances in curative strategies, will our current sensitive assays provide sufficient confidence to stop HIV therapy in patients showing a near absence of HIV RNA and DNA? Looking ahead, to determine the effectiveness of curative strategies, our field will need to develop a more standardized assay system which is sensitive, efficient, less costly, and adoptable in local settings.

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