The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
...
Slide 1 of 50
Death of HIV?
Davey Smith, MD
Professor of Medicine
University of California San Diego
Slide 2 of 50
Which of these is likely an example of
a functional HIV cure?
1. The Berlin Patient
2. The Mississippi Baby
...
Slide 3 of 50
Which of these is an example of a
functional HIV cure strategy?
1. Therapeutic Vaccine
2. HDAC inhibitor the...
Slide 4 of 50
Which of these is an example of a “kick
and kill” HIV cure strategy?
1. Therapeutic Vaccine
2. HDAC inhibito...
Slide 6 of 50
Learning Objectives
After attending this presentation, learners will be
able to describe:
Slide 7 of 50
Thing 1: HIV Reservoir Persists during ART
Limit of detection
Circulatingvirus
Time
START STOP
HAART
Antiret...
Slide 8 of 50
Thing 2
• The HIV Reservoir is Stable during ART
Slower-than-exponential decay of HIV-1 DNA during the first...
Slide 9 of 50
Types of Cure
• Sterilizing vs. Functional cure
– Sterilizing: HIV is cleared everywhere.
– Functional: the ...
Slide 10 of 50
The Berlin Patient
Hütter G et al. N Engl J Med 2009;360:692-698.
CCR5 ∆∆32
CCR5 ∆∆32
No AML
No HIV
CCR5 WT...
Slide 11 of 50
Interruption of Long-term Treatment Started During
Primary Infection May Lead to Viremia Control
Sáez-Cirió...
Slide 12 of 50
Interruption of Long-term Treatment Started During
Primary Infection May Lead to Viremia Control
Sáez-Cirió...
Slide 13 of 50
Henrich T J et al. J Infect Dis. 2013;207:1694-1702
CCR5 ∆32
Lymphoma
HIV
CCR5 WT
The Boston Patients
No ch...
Slide 14 of 50
Henrich T J et al. J Infect Dis. 2013;207:1694-1702
CCR5 ∆32
Lymphoma
HIV
CCR5 WT
The Boston Patients
No ch...
Slide 15 of 50
Persaud D et al. N Engl J Med 2013;369:1828-1835.
The Mississippi Baby
Immediate ART
AZT-3TC-NVP
Maintained...
Slide 16 of 50
Persaud D et al. N Engl J Med 2013;369:1828-1835.
The Mississippi Baby
Immediate ART
AZT-3TC-NVP
Maintained...
Slide 17 of 50
“Do not judge me by my successes,
judge me by how many times I fell
down and got back up again.”
- Nelson M...
Slide 18 of 50
Current Efforts
• Eliminating latency (kick and kill)
– Kicking: HDACi
– Killing: Immunotoxins (3B3-PE38)
•...
Slide 19 of 50
HIV Replication
CD4
CCR5
Slide 20 of 50
HIV Replication
CD4
CCR5
CD4
CCR5 RNA
Slide 21 of 50
HIV Replication
CD4
CCR5
CD4
CCR5
CD4
CCR5RNA
DNA
Slide 22 of 50
HIV Replication
CD4
CCR5
CD4
CCR5
CD4
CCR5
CD4
CCR5RNA
DNA DNA
RNA
Slide 23 of 50
HIV Replication
CD4
CCR5
DNA
CD4
CCR5
CD4
CCR5
CD4
CCR5
CD4
CCR5
CD4
CCR5
Slide 24 of 50
Untreated HIV Infection
=
Rampant Pollination
Slide 25 of 50
ART
Stops HIV Replication
Slide 26 of 50
The Latent Problem
Latent reservoir 1 in a
million CD4+ T cells
ART
Slide 27 of 50
The Latency Problem
Richman et al. Science 2009
CD4CCR5
Slide 28 of 50
Find the Latently Infected Cell
Slide 29 of 50
Kicking the Reservoir
Slide 30 of 50
Use a Kick to Find Latently Infected Cells
Slide 31 of 50
Use a Kick to Find Latently Infected Cells
HDACi
IL-7, PD-1
Prostratin
Vaccines
SMAC
Slide 32 of 50
Use a Kick to Find Latently Infected Cells
Slide 33 of 50
Kick and Kill
HIV-specific immune response or
immunotoxin kills cells producing virus
ART will keep new cel...
Slide 34 of 50
NM Archin et al. Nature 487, 482-485 (2012) doi:10.1038/nature11286
Vorinostat (HDACi) Upregulates HIV
RNA ...
Slide 35 of 50
3B3-PE38 Kills vRNA-producing Cells Leads to a More
Rapid Reduction in vRNA Levels versus ART Only
Denton P...
Slide 36 of 50
Cutting Out Latent HIV
Ebina et al. Scientific Reports 3, doi:10.1038/srep02510 (2013)
Slide 37 of 50
Slide 38 of 50
Improving Host Immune
Response
Slide 39 of 50
Enhance HIV-specific Immune Response
Therapeutic Vaccines
• Concept: Induce control of HIV replication
in s...
Slide 40 of 50
SG Hansen et al. Nature 000, 1-5 (2013) doi:10.1038/nature12519
RhCMV/SIV Vector-Mediated Protection
• Live...
Slide 41 of 50
PD-1 Axis: Functional Cure
• PD-1: a negative regulator of activated T cells is
upregulated on exhausted vi...
Slide 42 of 50
PD-1 Axis: Functional Cure
APC
Energized
HIV-specific
T-cell
Increased
HIV
expression
Trautmann et al. Nat ...
Slide 43 of 50
PD-1 Axis: Functional Cure
Energized
HIV-specific
T-cell
Increased
HIV
expression
Trautmann et al. Nat Med ...
Slide 44 of 50
Making Cells Resistant to HIV
http://en.wikipedia.org/wiki/File:Repair_outcomes_of_a_genomic_double-strand_...
Slide 45 of 50
CCR5-Modified CD4 T Cells during Treatment Interruption
Did Not Decrease, Unlike Unmodified CD4 T Cells
Teb...
Slide 46 of 50
46
How do you know if you cured someone of HIV?
Slide 47 of 50
47
How do you know if you cured someone of HIV?
Stop ART
Virus does not
return= CURE
Slide 48 of 50
48
How do you know if you cured someone of HIV?
Stop ART
Virus returns
= DAMN
Slide 49 of 50
49
How do you know if you cured someone of HIV?
Stop ART
Virus returns
= DAMN
Are we on the right
track?
Slide 50 of 50
50
How do you know if you cured someone of HIV?
Stop ART
Virus returns
= DAMN
Are we on the right
track?We ...
Slide 51 of 50
51
How do you know if you cured someone of HIV?
Stop ART
Virus returns
= DAMN
Are we on the right
track?We ...
Slide 52 of 50
What can we learn from MAPs?
• Where we are
• Where we are going
• How we know if we are on the right track...
Slide 53 of 50
53
We Are Here
HIV Cure
We need a MAP
Slide 54 of 50
54
We Are Here
HIV Cure
Slide 55 of 50
How do we know if we are on the right track?
55
We Are Here
HIV Cure
Is there a biomarker that can predict ...
Slide 56 of 50
What does a biomarker do?
• Diagnostic
– Able to diagnose disease when present and exclude
disease when abs...
Slide 57 of 50
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
Proportion alive according to HIV RNA in copies /ml
Years since HIV RN...
Slide 58 of 50
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
Proportion alive according to HIV RNA in copies /ml
Years since HIV RN...
Slide 59 of 50
All MAPs Are Not Created Equal
59
10^100
Slide 60 of 50
60
SMART
MAP for Cure
Agenda
Timing of ART Re-initiation CD4<250 VL > threshold
Duration of Tx interrupt Pr...
Slide 61 of 50
The Biomarker MAP Study Goals
• Evaluate virologic, immunologic, and pharmacologic
biomarker predictors of ...
Slide 62 of 50
Proposed MAP Study
62
Slide 63 of 50
• How long will we have to wait?
Slide 64 of 50
• Mandela painted at the DDC. Courtesy of Organ Museum ©2011 www.AbodeofChaos.org
Slide 65 of 50
Slide 66 of 50
Which of these is likely an example of
a functional HIV cure?
1. The Berlin Patient
2. The Mississippi Baby...
Slide 67 of 50
Which of these is an example of a
functional HIV cure strategy?
1. Therapeutic Vaccine
2. HDAC inhibitor th...
Slide 68 of 50
Which of these is an example of a “kick
and kill” HIV cure strategy?
1. Therapeutic Vaccine
2. HDAC inhibit...
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The Latest on HIV Cure Strategies

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Davey Smith, MD, MAS, of UC San Diego AntiViral Research Center, presents "The Lastest on HIV Cure Strategies," at AIDS Clinical Rounds

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The Latest on HIV Cure Strategies

  1. 1. The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission. AIDS CLINICAL ROUNDS
  2. 2. Slide 1 of 50 Death of HIV? Davey Smith, MD Professor of Medicine University of California San Diego
  3. 3. Slide 2 of 50 Which of these is likely an example of a functional HIV cure? 1. The Berlin Patient 2. The Mississippi Baby 3. The Boston Patients 4. The Visconti Cohort
  4. 4. Slide 3 of 50 Which of these is an example of a functional HIV cure strategy? 1. Therapeutic Vaccine 2. HDAC inhibitor therapy 3. PD-1 blockade 4. CRISPR HIV DNA modification
  5. 5. Slide 4 of 50 Which of these is an example of a “kick and kill” HIV cure strategy? 1. Therapeutic Vaccine 2. HDAC inhibitor therapy 3. CRISPR HIV DNA modification 4. CCR5 gene deletions
  6. 6. Slide 6 of 50 Learning Objectives After attending this presentation, learners will be able to describe:
  7. 7. Slide 7 of 50 Thing 1: HIV Reservoir Persists during ART Limit of detection Circulatingvirus Time START STOP HAART Antiretroviral drugs are capable of suppressing HIV to undetectable levels HIV rebounds after stopping therapy HIV infection is characterized by high levels of circulating viruses in the blood
  8. 8. Slide 8 of 50 Thing 2 • The HIV Reservoir is Stable during ART Slower-than-exponential decay of HIV-1 DNA during the first 4 years of ART Strain M C et al. J Infect Dis. 2005;191:1410-1418
  9. 9. Slide 9 of 50 Types of Cure • Sterilizing vs. Functional cure – Sterilizing: HIV is cleared everywhere. – Functional: the host’s immune system is able to control HIV infection without help from ART.
  10. 10. Slide 10 of 50 The Berlin Patient Hütter G et al. N Engl J Med 2009;360:692-698. CCR5 ∆∆32 CCR5 ∆∆32 No AML No HIV CCR5 WT AML HIV SCT x 2 Chemo and Rad GVHD
  11. 11. Slide 11 of 50 Interruption of Long-term Treatment Started During Primary Infection May Lead to Viremia Control Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211.
  12. 12. Slide 12 of 50 Interruption of Long-term Treatment Started During Primary Infection May Lead to Viremia Control Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. •PTCs may not be rare •15% of VISCONTI cohort •PTCs also identified in ACTG ATI studies of patients treated during acute and chronic infection. •What proportion of patients are PTCs? •What is special about PTCs?
  13. 13. Slide 13 of 50 Henrich T J et al. J Infect Dis. 2013;207:1694-1702 CCR5 ∆32 Lymphoma HIV CCR5 WT The Boston Patients No chemo or rad ART Stopped lymphocyte
  14. 14. Slide 14 of 50 Henrich T J et al. J Infect Dis. 2013;207:1694-1702 CCR5 ∆32 Lymphoma HIV CCR5 WT The Boston Patients No chemo or rad ART Stopped Henrich T J et al. CROI 2014 lymphocyte
  15. 15. Slide 15 of 50 Persaud D et al. N Engl J Med 2013;369:1828-1835. The Mississippi Baby Immediate ART AZT-3TC-NVP Maintained ART AZT-3TC-LPV-r For 18 months
  16. 16. Slide 16 of 50 Persaud D et al. N Engl J Med 2013;369:1828-1835. The Mississippi Baby Immediate ART AZT-3TC-NVP Maintained ART AZT-3TC-LPV-r For 18 months Rebound 3 years later 16k VL
  17. 17. Slide 17 of 50 “Do not judge me by my successes, judge me by how many times I fell down and got back up again.” - Nelson Mandela
  18. 18. Slide 18 of 50 Current Efforts • Eliminating latency (kick and kill) – Kicking: HDACi – Killing: Immunotoxins (3B3-PE38) • Enhance HIV-specific immune response – Therapeutic vaccines, anti-PD-1 axis • Making cells resistant to HIV – Gene therapy
  19. 19. Slide 19 of 50 HIV Replication CD4 CCR5
  20. 20. Slide 20 of 50 HIV Replication CD4 CCR5 CD4 CCR5 RNA
  21. 21. Slide 21 of 50 HIV Replication CD4 CCR5 CD4 CCR5 CD4 CCR5RNA DNA
  22. 22. Slide 22 of 50 HIV Replication CD4 CCR5 CD4 CCR5 CD4 CCR5 CD4 CCR5RNA DNA DNA RNA
  23. 23. Slide 23 of 50 HIV Replication CD4 CCR5 DNA CD4 CCR5 CD4 CCR5 CD4 CCR5 CD4 CCR5 CD4 CCR5
  24. 24. Slide 24 of 50 Untreated HIV Infection = Rampant Pollination
  25. 25. Slide 25 of 50 ART Stops HIV Replication
  26. 26. Slide 26 of 50 The Latent Problem Latent reservoir 1 in a million CD4+ T cells ART
  27. 27. Slide 27 of 50 The Latency Problem Richman et al. Science 2009 CD4CCR5
  28. 28. Slide 28 of 50 Find the Latently Infected Cell
  29. 29. Slide 29 of 50 Kicking the Reservoir
  30. 30. Slide 30 of 50 Use a Kick to Find Latently Infected Cells
  31. 31. Slide 31 of 50 Use a Kick to Find Latently Infected Cells HDACi IL-7, PD-1 Prostratin Vaccines SMAC
  32. 32. Slide 32 of 50 Use a Kick to Find Latently Infected Cells
  33. 33. Slide 33 of 50 Kick and Kill HIV-specific immune response or immunotoxin kills cells producing virus ART will keep new cells from being infected CTL
  34. 34. Slide 34 of 50 NM Archin et al. Nature 487, 482-485 (2012) doi:10.1038/nature11286 Vorinostat (HDACi) Upregulates HIV RNA Expression
  35. 35. Slide 35 of 50 3B3-PE38 Kills vRNA-producing Cells Leads to a More Rapid Reduction in vRNA Levels versus ART Only Denton PW, Long JM, Wietgrefe SW, Sykes C, et al. (2014) Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART. PLoS Pathog 10(1): e1003872. doi:10.1371/journal.ppat.1003872
  36. 36. Slide 36 of 50 Cutting Out Latent HIV Ebina et al. Scientific Reports 3, doi:10.1038/srep02510 (2013)
  37. 37. Slide 37 of 50
  38. 38. Slide 38 of 50 Improving Host Immune Response
  39. 39. Slide 39 of 50 Enhance HIV-specific Immune Response Therapeutic Vaccines • Concept: Induce control of HIV replication in someone who is already infected. • ALVAC-HIV-recombinant canarypox: made things worse. • Rh-CMV/SIV vector • PD-1 axis Autran et al. AIDS 2008
  40. 40. Slide 40 of 50 SG Hansen et al. Nature 000, 1-5 (2013) doi:10.1038/nature12519 RhCMV/SIV Vector-Mediated Protection • Live RhCMV vectors that contain SIV genes (SIV Gag, Rev/Tat/Nef, Env and Pol) establish persistent, SIV-specific effector memory T- cell (TEM) responses in rhesus macaques and control SIV infection.
  41. 41. Slide 41 of 50 PD-1 Axis: Functional Cure • PD-1: a negative regulator of activated T cells is upregulated on exhausted virus-specific CD8 T cells. • Blockade of this pathway using antibodies against the PD- 1 and PD-1 ligand 1 restores CD8 T-cell function and reduces viral load. APC Exhausted HIV-specific T-cell Latently infected T-cell Trautmann et al. Nat Med 2006; Day et al. Nature 2006 PD-1 PD 1-L
  42. 42. Slide 42 of 50 PD-1 Axis: Functional Cure APC Energized HIV-specific T-cell Increased HIV expression Trautmann et al. Nat Med 2006; Day et al. Nature 2006 PD-1 PD 1-L
  43. 43. Slide 43 of 50 PD-1 Axis: Functional Cure Energized HIV-specific T-cell Increased HIV expression Trautmann et al. Nat Med 2006; Day et al. Nature 2006 Increased CTL activity Increase HIV CTL+ Identify latently infected cells= Decrease reservoir =Functional Cure? APC PD-1 PD 1-L
  44. 44. Slide 44 of 50 Making Cells Resistant to HIV http://en.wikipedia.org/wiki/File:Repair_outcomes_of_a_genomic_double-strand_break_for_ZFN_cleavage.jpg CD4CCR5 CCR5 CD4 X Take out CCR5 gene Zinc Finger Nucleases
  45. 45. Slide 45 of 50 CCR5-Modified CD4 T Cells during Treatment Interruption Did Not Decrease, Unlike Unmodified CD4 T Cells Tebas P et al. N Engl J Med 2014;370:901-910.
  46. 46. Slide 46 of 50 46 How do you know if you cured someone of HIV?
  47. 47. Slide 47 of 50 47 How do you know if you cured someone of HIV? Stop ART Virus does not return= CURE
  48. 48. Slide 48 of 50 48 How do you know if you cured someone of HIV? Stop ART Virus returns = DAMN
  49. 49. Slide 49 of 50 49 How do you know if you cured someone of HIV? Stop ART Virus returns = DAMN Are we on the right track?
  50. 50. Slide 50 of 50 50 How do you know if you cured someone of HIV? Stop ART Virus returns = DAMN Are we on the right track?We need a MAP
  51. 51. Slide 51 of 50 51 How do you know if you cured someone of HIV? Stop ART Virus returns = DAMN Are we on the right track?We need a MAPYou are here http://upload.wikimedia.org/wikipedia/commons/a/a8/8_Observable_Universe_%28ELitU%29.png
  52. 52. Slide 52 of 50 What can we learn from MAPs? • Where we are • Where we are going • How we know if we are on the right track 52
  53. 53. Slide 53 of 50 53 We Are Here HIV Cure We need a MAP
  54. 54. Slide 54 of 50 54 We Are Here HIV Cure
  55. 55. Slide 55 of 50 How do we know if we are on the right track? 55 We Are Here HIV Cure Is there a biomarker that can predict incremental success of an HIV cure eradication?
  56. 56. Slide 56 of 50 What does a biomarker do? • Diagnostic – Able to diagnose disease when present and exclude disease when absent • Predictive and Prognostic – Able to predict future or course of disease – Able to predict treatment response – Common problem: associative vs. predictive Courtesy of Scott Letendre -The Biomarkers Consortium Foundation of the NIH
  57. 57. Slide 57 of 50 0 2 4 6 8 10 0.0 0.2 0.4 0.6 0.8 1.0 Proportion alive according to HIV RNA in copies /ml Years since HIV RNA quantification (bDNA) <500 500 to 3,000 3,001 to 10,000 10,001 to 30,000 >30,000
  58. 58. Slide 58 of 50 0 2 4 6 8 10 0.0 0.2 0.4 0.6 0.8 1.0 Proportion alive according to HIV RNA in copies /ml Years since HIV RNA quantification (bDNA) <500 500 to 3,000 3,001 to 10,000 10,001 to 30,000 >30,000 If you have a biologically relevant biomarker, then you do not have to have a body count to assess if something worked.
  59. 59. Slide 59 of 50 All MAPs Are Not Created Equal 59 10^100
  60. 60. Slide 60 of 50 60 SMART MAP for Cure Agenda Timing of ART Re-initiation CD4<250 VL > threshold Duration of Tx interrupt Prolonged Short Post-ATI Monitoring Monthly 2-3x per week Repeated Tx interrupt cycles? Yes No
  61. 61. Slide 61 of 50 The Biomarker MAP Study Goals • Evaluate virologic, immunologic, and pharmacologic biomarker predictors of HIV rebound; • Develop a standardized MAP protocol for future studies; • Describe time to rebound across broad patient groups; • Identify potential mechanisms of HIV persistence; • Delineate importance of anatomic and cellular reservoirs; • Characterize rebounding virus so it can be targeted; • Produce a biorepository to speed assay development; • Determine frequency and predictors of post-treatment control. 61
  62. 62. Slide 62 of 50 Proposed MAP Study 62
  63. 63. Slide 63 of 50 • How long will we have to wait?
  64. 64. Slide 64 of 50 • Mandela painted at the DDC. Courtesy of Organ Museum ©2011 www.AbodeofChaos.org
  65. 65. Slide 65 of 50
  66. 66. Slide 66 of 50 Which of these is likely an example of a functional HIV cure? 1. The Berlin Patient 2. The Mississippi Baby 3. The Boston Patients 4. The Visconti Cohort
  67. 67. Slide 67 of 50 Which of these is an example of a functional HIV cure strategy? 1. Therapeutic Vaccine 2. HDAC inhibitor therapy 3. PD-1 blockade 4. CRISPR HIV DNA modification
  68. 68. Slide 68 of 50 Which of these is an example of a “kick and kill” HIV cure strategy? 1. Therapeutic Vaccine 2. HDAC inhibitor therapy 3. CRISPR HIV DNA modification 4. CCR5 gene deletions

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