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

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Death of HIV?
Davey Smith, MD
Professor of Medicine
University of California San Diego

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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

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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

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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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Learning Objectives
After attending this presentation, learners will be
able to describe:

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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

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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

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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.

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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

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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.

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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?

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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

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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

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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

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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

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“Do not judge me by my successes,
judge me by how many times I fell
down and got back up again.”
- Nelson Mandela

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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

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HIV Replication
CD4
CCR5

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HIV Replication
CD4
CCR5
CD4
CCR5 RNA

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HIV Replication
CD4
CCR5
CD4
CCR5
CD4
CCR5RNA
DNA

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HIV Replication
CD4
CCR5
CD4
CCR5
CD4
CCR5
CD4
CCR5RNA
DNA DNA
RNA

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HIV Replication
CD4
CCR5
DNA
CD4
CCR5
CD4
CCR5
CD4
CCR5
CD4
CCR5
CD4
CCR5

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Untreated HIV Infection
=
Rampant Pollination

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ART
Stops HIV Replication

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The Latent Problem
Latent reservoir 1 in a
million CD4+ T cells
ART

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The Latency Problem
Richman et al. Science 2009
CD4CCR5

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Find the Latently Infected Cell

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Kicking the Reservoir

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Use a Kick to Find Latently Infected Cells

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Use a Kick to Find Latently Infected Cells
HDACi
IL-7, PD-1
Prostratin
Vaccines
SMAC

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Kick and Kill
HIV-specific immune response or
immunotoxin kills cells producing virus
ART will keep new cells
from being infected
CTL

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NM Archin et al. Nature 487, 482-485 (2012) doi:10.1038/nature11286
Vorinostat (HDACi) Upregulates HIV
RNA Expression

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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

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Cutting Out Latent HIV
Ebina et al. Scientific Reports 3, doi:10.1038/srep02510 (2013)

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Improving Host Immune
Response

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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

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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.

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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

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APC
Energized
HIV-specific
T-cell
Increased
HIV
expression
PD-1
PD
1-L

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Energized
HIV-specific
T-cell
Increased
HIV
expression
Increased
CTL activity
Increase HIV CTL+
Identify latently
infected cells=
Decrease reservoir
=Functional Cure?
APC
PD-1
PD
1-L

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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

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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.

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46
How do you know if you cured someone of HIV?

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47
Stop ART
Virus does not
return= CURE

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48
Stop ART
Virus returns
= DAMN

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49
Stop ART
Virus returns
= DAMN
Are we on the right
track?

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50
Stop ART
Virus returns
= DAMN
Are we on the right
track?We need a MAP

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51
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

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What can we learn from MAPs?
• Where we are
• Where we are going
• How we know if we are on the right track
52

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53
We Are Here
HIV Cure
We need a MAP

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54
We Are Here
HIV Cure

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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?

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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

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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

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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.

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All MAPs Are Not Created Equal
59
10^100

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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

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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

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Proposed MAP Study
62

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• How long will we have to wait?

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