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 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

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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

CCR5 RNA

DNA

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HIV Replication

CD4

CCR5 CD4

CCR5

CD4

CCR5

CD4

CCR5 RNA

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

CD4 CCR5

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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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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

PD1-L

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PD-1 Axis: Functional Cure

APC

Energized HIV-specific T-cell

Increased HIV expression


PD-1

PD1-L

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PD-1 Axis: Functional Cure

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

PD1-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

CD4 CCR5

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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How do you know if you cured someone of HIV?

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Stop ART Virus does not return= CURE

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Stop ART Virus returns = DAMN

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Are we on the right track?

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Are we on the right track? We need a MAP

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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

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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

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We Are Here

HIV Cure

We need a MAP

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We Are Here

HIV Cure

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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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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.

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Proposed MAP Study

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• How long will we have to wait?

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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

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

the latest on hiv cure strategies

Health & Medicine

hiv reservoir

death of hiv

lymphoma hiv ccr5 wt

therapy hiv infection

hiv ccr5 wt aml hiv

hiv gene therapy

untreated hiv infection

art stops hiv replication