Download - The Latest on HIV Cure Strategies
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
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 3. The Boston Patients 4. The Visconti Cohort
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
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
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 Circ
ulat
ing
viru
s
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
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
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.
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
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.
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?
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
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
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
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
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
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
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
CCR5 RNA
DNA
Slide 22 of 50
HIV Replication
CD4
CCR5 CD4
CCR5
CD4
CCR5
CD4
CCR5 RNA
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
CD4 CCR5
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 cells from being infected
CTL
Slide 34 of 50
NM Archin et al. Nature 487, 482-485 (2012) doi:10.1038/nature11286
Vorinostat (HDACi) Upregulates HIV RNA Expression
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
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 someone who is already infected.
• ALVAC-HIV-recombinant canarypox: made things worse.
• Rh-CMV/SIV vector • PD-1 axis
Autran et al. AIDS 2008
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.
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
PD1-L
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
PD1-L
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
PD1-L
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
CD4 CCR5
CCR5 CD4 X
Take out CCR5 gene
Zinc Finger Nucleases
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.
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 need a MAP
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 MAP You are here
http://upload.wikimedia.org/wikipedia/commons/a/a8/8_Observable_Universe_%28ELitU%29.png
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
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 incremental success of
an HIV cure eradication?
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
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
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.
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 Prolonged Short Post-ATI Monitoring Monthly 2-3x per week Repeated Tx interrupt cycles? Yes No
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
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 3. The Boston Patients 4. The Visconti Cohort
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
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