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AIDS CLINICAL ROUNDS

The State of the Art in HIV Cure

Research— Hope or Hype

Joseph J. Eron, Jr., MD Professor of Medicine

The University of North Carolina

Disclosures

• Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from Argos, Bristol-Myers Squibb, GlaxoSmithKline/ViiV, Gilead Sciences, Janssen, Kainos, Koronis, Merck, and Tobira; has served on the data and safety monitoring board for Vertex; and has served as a principal investigator for research with funds paid to the University of North Carolina from Bristol-Myers Squibb, GlaxoSmithKline/ViiV, and Tobira.

What percentage of your patients have asked whether

HIV can be cured?

1. < 5% 2. 5%-25% 3. 25%-75% 4. Almost everyone has asked at one time

or another

Why Cure HIV? • Shortened life expectancy of HIV-infected

persons, even with treated HIV infection[1]

• Cost, consequences (known and unknown) and the impact on QOL of antiretroviral therapy[2]

– ART needed for decades of life with high level of adherence[2]

• Stigma, discrimination, fear of transmission, isolation[3]

• Global burden of HIV-1 disease[4]

1. Lohse N, et al. Ann Intern Med. 2007;146:87-95. 2. Volberding PA, et al. Lancet. 2010;376:49-62. 3. Parker R, et al. Soc Sci Med. 2003;57:13-24. 4. Mathers CD, et al. PLoS Med. 2006;3:e442.

HIV-1 CAN BE CURED

The State of the Art in HIV Cure Research— Hope or Hype

CAN HIV-1 BE CURED? Berlin Patient

Hütter G, et al. N Engl J Med. 2009;360:692-698.

Substantial graft vs host disease

1. Hütter G, et al. N Engl J Med. 2009;360:692-698. 2. Allers K, et al. Blood. 2011;117:2791-2799.

Yukl et al PLoS Pathogens May 2013

Challenges in Detecting HIV Persistence during Potentially Curative Interventions: A Study of The Berlin Patient

Original Article: Brief Report Absence of Detectable HIV-1

Viremia after Treatment Cessation in an Infant

Deborah Persaud, M.D., Hannah Gay, M.D., Carrie Ziemniak, M.S., Ya Hui Chen, B.A., Michael Piatak, Jr., Ph.D., Tae-Wook Chun, Ph.D., Matthew Strain, M.D., Ph.D.,

Douglas Richman, M.D., and Katherine Luzuriaga, M.D.

N Engl J Med Volume 369(19):1828-1835

November 7, 2013

Very Early Triple-Drug ART Elicits “Potential Cure” in HIV-Infected Child Infant born to untreated HIV-infected mother at 35 wks’

gestation via spontaneous vaginal delivery[1]

– Maternal HIV infection identified during labor via ELISA and Western blot

– Infant HIV infection confirmed via HIV-1 DNA PCR, HIV-1 RNA analysis of 2 separate samples at 30 and 31 hrs of age[2]

– ZDV/3TC + NVP (at therapeutic dose) initiated at 31 hrs of age, continued for 7 days

– ZDV/3TC + LPV/RTV continued from 7 days to 18 mos of age

– HIV-1 RNA undetectable by Day 30

– Mother removed patient from care at 18 mos of age

1. Persaud D, et al. CROI 2013. Abstract 48LB. 2. DHHS Pediatric Guidelines. 2012.

“Potential Cure” Child: Standard HIV-1 Assays Undetectable to Age 26 Mos

Assessments at Mos 24, 26

– Western blot negative

– No HIV-specific CD8+ or CD4+ T-cell responses

Standard HIV-1 RNA and HIV-1 DNA undetectable

Ultrasensitive assays

– Mo 24: HIV-1 RNA 1 c/mL; HIV-1 DNA 37 c/million PBMCs

– Mo 26: HIV-1 DNA < 2.7 c/million PBMCs

Persaud D, et al. CROI 2013. Abstract 48LB

HIV

-1 R

NA

(cop

ies/

mL)

105

104

103

102

101

0 20 40 60 80 100

Age (days)

19,812 c/mL (4.3 log)

Closed symbols = Detectable HIV-1 RNA Open symbols = Undetectable HIV-1 RNA

2617 c/mL (3.4 log)

516 c/mL (2.7 log)

265 c/mL (2.4 log)

< 48 c/mL (<1.68 log)

ZDV/3TC + NVP 31 hours – 7 days

ZDV/3TC + LPV/RTV 7 days – 18 months

Biphasic Decay in Plasma Viral Load on ART

Specialized Studies to Assess Persistence of HIV-1 Infection in the Child.

Persaud D et al. N Engl J Med 2013;369:1828-1835

CURING HIV WILL BE DIFFICULT The State of the Art in HIV Cure Research— Hope or Hype

“Boston Patients” Two HIV+ patients who underwent allogeneic hematopoietic stem cell transplant

Both failed conventional therapy for lymphoma Reduced-intensity conditioning; no total body irradiation, no ATG Both had graph vs. host disease Donors CCR5 wild-type; recipients achieved full donor chimerism

No detectable HIV reservoirs in blood or rectal tissue (2-4 yrs after HSCT)

Henrich T, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract WeLBA05. Henrich TJ, et al. J Infect Dis. 2013;207:1694-1702. Henrich T et al CROI 2014 #144LB

Long-Term PBMC DNA and CD4 Count Following RIC-alloHSCT

Henrich T, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract WeLBA05. HSCT: hematopoietic stem cell transplantation.

Patient A: PBMC DNA CD4 Count

Post HSCT (days) 0 200 400 600 800 1000 1200 1400 1600

HIV

DN

A (c

opie

s/10

6 PB

MC

)

Post HSCT (days) 0 200 400 600 800 1000 1200 1400 1600

CD

4 (c

ells

/mm

3 ) 4.3 Years

Post-HSCT (<0.07 copies/106)

HCST

100% Donor Lymphocyte Chimerism

Patient B: PBMC DNA CD4 Count

Post HSCT (days) 0 200 400 600 800 1000 1200 1400 1600

HIV

DN

A (c

opie

s/10

6 PB

MC

)

Post HSCT (days) 0 200 400 600 800 1000 1200 1400 1600

CD

4 (c

ells

/mm

3 )

2.6 Years Post-HSCT

(<0.04 copies/106)

HCST

100% Donor Lymphocyte Chimerism

Long-Term Reduction in Peripheral Blood HIV-1 Reservoirs Following RIC-alloHSCT

● ART in the context of RIC-alloHSCT is well tolerated

● More extensive testing in the setting of full donor chimerism failed to identify evidence of HIV-1 infection of donor cells

- Viral outgrowth assays and qPCR incorporating large PBMC or CD4 cell quantities

- HIV-1 DNA from rectal tissue

● No evidence for HIV-specific cellular immune responses

● Implications - Donor cells in various tissues are

protected from infection by ongoing ART

Henrich T, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract WeLBA05.

*6 weeks (results from patient A pending). ATI: analytical treatment interruption. SCA: single-copy RNA assay. RIC-alloHSCT: reduced intensity allogeneic hematopoietic stem cell transplantation.

Additional/Ongoing Results

Patient A Patient B Post-HSCT Highly sensitive PCR-based chimerism

Host cells: 0.00041% to 0.00081% of

PBMCs

Host cells: 0.00035% to 0.00096%of

PBMCs

Immune response HIV-specific (INF-γ ELISpot) Other

None

None

None

CMV/EBV/ Influenza

ATI HIV plasma RNA PBMC DNA SCA* Proviral DNA*

7 weeks Not detectable Not detectable

-- --

15 weeks Not detectable Not detectable Not detectable Not detectable

Analytical Treatment Interruption

Patient

Tacrolimus GVHD txt during ATI

Analytical Treatment Interruption Patient

What Should “Cure” Look Like? • BMT too toxic, too dangerous, and too

expensive for most infected individuals

– For patients who need BMT, though, cure can and should be a goal

• Treatment for cure must be time limited, tolerable and have limited risk

• May be expensive – Modest success rate may be cost-saving

• Many hurdles but we have to start somewhere

Barriers to Cure • Low level viremia detectable in most ARV

treated patients[1]

• Residual viral replication?[2]

• Potential pharmacologic reservoirs[2]

• Latently infected cells[2,3]

• Resting CD4+ T cells which replenish [2,3]

• Other (potential) cell types [2,3]

• Long-lived cells (macrophage, microglia) [3]

• Failure of HIV-specific immunity and generalized immune dysfunction[4]

1. Palmer S, et al Proc Natl Acad Sci 2008 105:3879-84. 2. Johnston R, et al. J Int AIDS Soc. 2012;15:16. 3. Richman DD, et al. Science. 2009;323:1304-1307. 4. Kaufmann DE, et al. J HIV Ther. 2003;8:19-25.

Patients Treated During Acute HIV Infection Enhance the opportunity for Cure?

• Most individuals are infected with a single viral variant or a few highly related variants[1]

• CTL responses occur very early and can be robust • HIV-specific CD4-cell responses may be preserved by early

therapy[2]

• Persistent activation may be diminished • HIV reservoirs may be smaller and appears be inversely

related to replication AUC[3,4]

• Effective therapy stops viral evolution and appears to fix early variants in latent reservoir[5]

1. Abrahams M-R, et al. J Virol. 2009;83:3556-3567. 2. Oxenius A, et al. Proc Natl Acad Sci USA. 2000;97:3382-3387. 3. Ananworanich J, et al. 5th International Workshop on HIV Persistence During Therapy. 2011. Abstract 32. 4. Archin et al PNAS 2012 5. Anderson et al J Virol 2011

Reservoir Size in Treated AHI Model including VL, CD4 and latent cell decay

Archin … Margolis, Perelson PNAS 2012

clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013

Early Treatment of Pts With Acute HIV Infection Restricts Seeding of Reservoirs RV254/SEARCH 010: ongoing, prospective, open-label study of subjects

seeking voluntary HIV testing (n = 75 with Fiebig stage I-III acute infection)

Before ART, HIV reservoir seeding limited

– Integrated HIV DNA undetectable in PBMCs (92%) and sigmoid colon (88%) of most Fiebig I pts

– Lower infection frequencies of central memory CD4+ T cells vs other memory cells

After ART, decline in HIV reservoir size

– Integrated HIV DNA undetectable in PBMCs in 90% of pts at 1 yr

– Reservoir primarily in transitional and effector memory CD4+ T cells

Suggests very early ART may prevent seeding of reservoirs

Fiebig Stages

Fiebig I: RNA+, p24̶ neg, 3rd gen ELISA-neg

– Would not be detected by 4th gen ELISA

Fiebig II: RNA+, p24+; 3rd gen ELISA-neg

Fiebig III: 3rd gen ELISA+, WB-neg Ananworanich J, et al. CROI 2013. Abstract 47.

Fiebig I

Integrated HIV DNA at 24 weeks after ART

Not detected

Chronic HIV

Not detected

Fiebig III

Limited viral diversification in virus from plasma and resting CD4 cells 5 years after treated acute HIV infection.

Anderson et al J Virol 2011

Barriers to Cure • Low level viremia detectable in most ARV

treated patients[1]

• Residual viral replication?[2]

• Potential pharmacologic reservoirs[2]

• Latently infected cells[2,3]

• Resting CD4+ T cells which replenish [2,3]

• Other (potential) cell types [2,3]

• Long-lived cells (macrophage, microglia) [3]

• Failure of HIV-specific immunity and generalized immune dysfunction[4]

1. Palmer S, et al Proc Natl Acad Sci 2008 105:3879-84. 2. Johnston R, et al. J Int AIDS Soc. 2012;15:16. 3. Richman DD, et al. Science. 2009;323:1304-1307. 4. Kaufmann DE, et al. J HIV Ther. 2003;8:19-25.

HIV-1 in the “Suppressed” Patient

• Latent virus reservoir • Virus expressing reservoir

– > 70% of “suppressed” patients have detectable viremia • Latent cells intermittently activate? • Persistent shedding from macrophage or other

long lived cells? • Ongoing replication?

Palmer et al, Maldarelli F, et al. PLoS Pathog. 2007;3:e46. Riddler et al CROI 2014

HIV-1 RNA Diversity

No Sequence Evolution after 7 years on cART Emergence of a Predominant Plasma Clone (PPC)

After Years on ART

0.005

Days on ART -20 0 20 40 60 10 1

10 2

10 3

10 4

10 5

10 6

0.0

0.5

1.0

1.5

2.0

2.5

3.0

1500 1750 2000

HIV

-1 R

NA

(cop

ies/

mL)

Diversity (%

)

Start ART

2250

3.5 10 7

Kearney M, et al. Unpublished data used with permission.

0.0001 0.001 0.01 0.1

1 10

100 1000

10000

0 1 2 3 4 5 6 7 Time on HAART (years)

Freq

uenc

y (p

er 1

06 c

ells

) Resting CD4+ Cell Infection Extremely

Stable Despite ART

-

Time to eradication > 73.4 years

0.00001

1. Finzi D, et al. Science. 1997;278:1295-1300. 5. Siliciano JD, et al. Nature Med. 2003;9:727-728. 2. Wong JK, et al. Science. 1997;278:1291-1295. 6. Chun TW, et al. Nature Med. 1995;1:1284-1290. 3. Chun TW, et al. PNAS. 1997;94:13193-13197. 7. Chun TW, et al. Nature. 1997;387:183:188. 4. Finzi D, et al. Nature Med. 1999;5:512-517.

New Explanations for HIV Persistence

• Infection and persistence in long-lived CD4+ T memory stem cells1

• Homeostatic proliferation of infected cells may sustain the HIV reservoir2

• Integration of HIV into cancer genes which may

give infected clones a survival advantage3

1Lichterfeld M et al, CROI 2014, #54; 2Wagner T et al, CROI #138; 3Maldarelli F et al, CROI 2014, # 407LB

Other Challenges: •Clearance of infected cells •Clearance of virions •Complete block of new infection

Step 1: Eliminate Latent HIV Infection From Resting CD4+

Cells

Anti-latency therapy

1. Rong L, et al. PLoS Comput Biol. 2009;5:e1000533. 2. Lewin SR, et al. AIDS. 2011;25:885-897.

Potential Interventions to Disrupt Latency

Richman DD, et al. Science. 2009;323:1304-1307.

“Open” Histones Acetylated Histone tails

Reduced Higher Order Structure Access to Transcription Factors

Transcription Active

“Closed” Nucleosome Hypo-Acetylated Histone tails

Stable, Compact Chromatin Less accessible to Transcription Factors

Transcription Repressed

deacetylated

acetylated

HIV lives within chromatin: tipping the balance towards acetylation removes a restriction at the initiation of proviral expression

Schiralli Lester GM, et al. Mol Biol Int. 2012;2012:614120.

Single 400 mg VOR dose: Remeasure resting CD4+ T cell HIV RNA expression. Define potential for VOR to disrupt latency

Mean 4.8-fold induction (range 1.5- to 10-fold) All increases

significant (P < .01) No AE > Grade I

No AE due to

VOR Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt.

8

HIV

-1 g

ag R

NA

copi

es p

er w

ell

Archin NM, et al. Nature. 2012;487:482-485.

HDAC Inhibitors Selected for Clinical Trials in HIV+ Subjects on ART

Vorinostat SAHA

Romidepsin Panobinostat

Structure

Regulatory Status FDA Approved FDA Approved Phase 3

Indication CTCL CTCL MM/AML

Dose 400 mg QD PO 14 mg/m2 IV Days 1, 8, 15 (28 day cycle)

20 mg TIW PO

Clinical studies in HIV+ Subjects

Underway (US & Australia)

Clinical protocol development (US-ACTG)

Enrolling (Denmark)

Dose / Duration 400 mg (single & 14 days)

< 14 mg/m2 SAD

20 mg TIW every other week /

8 weeks

NH

HN

NH

O

OH

Wei G, et al. CROI 2013. Abstract 376.

Slide 42

In Vitro Activation of HIV by HDAC Inhibitors

-11 -10 -9 -8 -7 -6 -5 -40

1×1005

2×1005

3×1005

Concentrations [Log10, M]

Luci

fera

se s

igna

l (R

LU) EC50

(nM) CC50

(nM) %max

Romidepsin 4.49 107 98% Panobinostat 10.1 > 2,500 108% Givinostat 95.8 24,000 79% SB939 212 > 50,000 104% Vorinostat 3,950 > 25,000 100% Mocetinostat 13,600 10,100 75%

RMD and Panobinostat approximately 400-900X more potent than Vorinostat

Will HDACi be Enough? • Not all studies show induction of viral

expression by HDACi ex vivo

• Combinations of anti-latency compounds with different mechanism of action may be more effective[1]

• Latently infected cells that express HIV-1 RNA may not die![2]

1. Moreno S. Retrovirology. 2012;9:I16. 2. Persaud D, et al. J Virol. 2003;77:1659-1665.

Vorinostat and Cell Death

• Resting cells stimulated with vorinostat ex vivo did not die

• In a model system of latency CD8+ cells from most patients did not kill CD4 cells that expressed virus

Shan et al Immunity 2012

Presence of Non-induced Proviruses in Resting CD4+ Cells

• 12% of non-induced proviruses appear replication competent • Is reactivation a stochastic event? Can these pro-virus be reactivated or are

they buried? Ho Y-C, et al. Cell 155, 540–551, October 24, 2013.

Clones of Intact Non-induced Proviruses Have Similar p24 Kinetics

Ho Y-C, et al. Cell 155, 540–551, October 24, 2013.

“Kick and Kill” • When latency is disrupted, mechanisms to kill

virus-expressing cells may be needed – Augment HIV-1 specific immune response with HIV-1

vaccine prior to “kick”[1]

– Improve HIV-1 specific CD8 response through ex vivo manipulation[2]

• TCR enhancement[2]

– Infuse broadly neutralizing antibody or antibody primed for ADCC[3]

– Wake up “exhausted” HIV-1 specific cells[4]

• Anti PD1 or Anti PD-L1[4]

1. Pantaleo G, et al.. Nat Med. 2004;10:806-810. 2. Oxenius A, et al. Eur J Immunol. 2001;31:1115-1121. 3. Kwong PD, et al. Cold Spring Harb Perspect Med. 2011;1:a007278. 4. Freeman GJ, et al. J Exp Med. 2006;203:2223-2227.

Spontaneous or Induced Reversal of Latency

Stimulation and recruitment of

immune effector cells

Targeted antibody or antibody-drug

conjugate delivery

Y Y

Elimination of expressing

cells

No Infection of CD4+T-

cells

Modified from Romas Geleziunas et al.

Strategies to reduce and/or control HIV reservoirs

0%

20%

40%

60%

80%

100%

120%

0 2 4 6 8

Healthy Donor 01Healthy Donor 02Healthy Donor 03Elite Suppressor 01Elite Suppressor 02Elite Suppressor 04HAART Patient 03HAART Patient 05HAART Patient 06HAART Patient 12HAART Patient 16HAART Patient 17HAART Patient 18HAART Patient 19

Res

idua

l inf

ecte

d C

D4+

T c

ells

(%)

Days in co-culture

CD8+ T cells from patients on ART do not reliably kill latently infected CD4+ T cells after virus reactivation

Shan Immunity 2012

0%

20%

40%

60%

80%

100%

120%

1 2 3 4 5

HAART Patient 03

HAART Patient 05

HAART Patient 06

HAART Patient 16

HAART Patient 18

HAART Patient 19

Res

idua

l inf

ecte

d C

D4+

T c

ells

(%)

Days in co-culture

CD8+ T cells from patients on ART do not reliably kill latently infected CD4+ T cells after virus reactivation

Shan Immunity 2012

HAART Patient 19 HAART Patient 18 HAART Patient 16 HAART Patient 5 HAART Patient 3

HAART Patient 6

Pre-stimulation of CD8+ T Cells Enhanced CTL Responses

Shan et al Immunity 2012

Adapted from Freeman G. et.al., J Exp Med 2006.

Evidence supports blockade of the PD-1/PD-L1 pathway as a viable therapeutic strategy in chronic HIV infection

PD-L1

PD-1 PD-1 /-L1 Blockade

• Persistent antigenemia leads to T cell exhaustion

• PD-1 is a key inhibitory receptor affecting T-cell response – Elevated on virus-specific T-

cells in chronic HIV; – seen on both CD4+ and CD8+

subsets; – cells display exhausted

phenotype ex vivo • Blockade of PD-1/PD-L1

– Restores HIV-specific immune functions in vitro and ex vivo

– Reduces viremia and prolongs survival in animal models in vivo

Barrier to HIV eradication: T cell exhaustion and the PD-1 pathway

52

PD-L1 blockade in ARV suppressed SIVmac251-infected Rhesus Macaques

Hypothesis: – Treatment of ARV-suppressed SIV infected macaques with αPD-L1 should:

– restore SIV-specific T cell function. Subsequently, this may: – reduce the latent SIV reservoir – lead to host control of virus following interruption of ARV

1. Virus-specific T cell functionality, 2. Cell-associated viral DNA (latent reservoir) in tissues and periphery, 3. Virus recrudescence after cessation of ARV treatment.

Objectives: – Determine whether multiple doses of BMS-936559 affect:

PD-L1 blockade

Start ARV

BMS-936559 (8) Isotype control (5) 5 X 10mg/kg

6 weeks

ARV TI

Viral load rebound off ARV

Study design: SIV Infection

2 weeks

Kinetics of viral load rebound post-treatment interruption

• Half of BMS-936559-treated animals had rebound similar to isotype-treated animals • BMS-936559-responder group remained below 1000 cp/mL for >8 weeks • Two had undetectable VL for 3-4 weeks

LOQ at 50 SIV RNA copies/mL *

J. Whitney S. Sanisetty

BMS-936559

Isotype

ACTG 5326

Safety and immunotherapeutic activity of an anti-PD-L1 antibody (BMS-936559) in HIV-1 infected subjects on suppressive

ART: pilot phase II, 24 week, double-blind, placebo-controlled, ascending single

dose study

1. Barber D.L. et al. Nature. 2006; 2. Day CL. et.al. Nature. 2006; 3. Streeck H. PLOS Med. 2008; 4.Petrovas C. et.al. J Exp. Med. 2006; 5. Boni C. et.al. J Virol. 2007; 6. Golden-Mason L. et.al. J Virol. 2007; 7. Evans A. et.al. Hepatol. 2008; 8. Velu V. et al. Nature. 2009

Rationale for A5326

The PD-1 inhibitory receptor dampens T-cell responses and is a marker of immune exhaustion in chronic HIV and other viral infections

PD-1 and its natural ligand PD-L1 remain elevated in HIV-infected patients on suppressive ART

T cell exhaustion mediated by PD-1/PD-L1 may be a barrier to HIV eradication

Multifunctional, anti-viral CD28+ memory T cell responses after four doses of AGS-004 after treatment in acute infection

59

Impact of Env-Specific Immunotoxin on Residual Active HIV-1 Reservoirs

● Prospective trial of HIV-infected, humanized BLT mice - ART for 42 days, env-specific

immunotoxin (3B3-PE38) for 14 days (day 28-42)

- Tissue viral load (bone marrow, thymic organoid, spleen, lymph nodes, liver, lung, peripheral blood cells)

● Results - ART reduced HIV RNA in peripheral

blood and systemically - Env-specific immunotoxin further

reduced HIV RNA by • Up to 1000-fold in individual tissues • 0.8 log10 copies/mL systemically

- Mechanism of reduced HIV RNA • Loss of productively infected cells

Denton PW, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract TuAA0101.

No ART (n=68 samples)

10 mice

Log 1

0 HIV

RN

A co

pies

per

10

5 CD

4 or

Tot

al T

hym

ocyt

es

HIV RNA Levels: All Tissues

ART (n=99 samples)

15 mice

ART + 3B3-PE38

(n=40 samples) 6 mice

-2.9 log10*

*P<0.001.

-2.1 log10*

-0.8 log10*

Additional Cure Strategies

• Genetic modification of CD4+ cells to limit or stop HIV replication[1]

– eg, Zinc finger nuclease “excision” of CCR5 gene[1]

• Specific activation of HIV-infected resting memory cells using targeted nano-particles[2]

• IL-7 or IL-16 with ARV intensification[3] • Reduce residual activation/inflammation and

limit replication in tissue??

1. Berger EA. Curr Opin HIV AIDS. 2011;6:80-85. 2. Wayengera M. HIV AIDS Rev. 2011;10:1-8. 3. Beq S, et al. Eur Cytokine Netw. 2004;15:279-289.

Cure Studies In ACTG HIV-1 infected patients suppressed on ART

• A5315 – Single dose romidepsin

• A5326 – Anti-PD-L1 antibody – Single infusion

• A5337 – Sirolimus (rapamycin)

Will HIV Infection be Curable? • HIV-1 can be cured in rare situations

– Bone marrow transplant (with resistant cells?) – Very early infection in infants (and maybe adults?)

• Substantial barriers to scalable curative treatments exist – Latently infected cells that sustain themselves – The possibility of ongoing replication – Inflammation may contribute to both of the above – Tissue or cellular sanctuaries (especially brain?)

• However – initial steps have been taken • Improvement in assays, medications and medical technology • Modestly effective therapy (30% cure) can be very cost

effective

Acknowledgements • David Margolis • JoAnn Kuruc • Victor Garcia • John Mellors • Mike Cohen • Mary Kearney • Joe Wong • Bob Siliciano • Steve Mason • Steve Deeks

Volunteers across all cure studies for their altruism and bravery

Thanks to all the patients participating in cure research!

“Post-Treatment Controllers” in ANRS Visconti Cohort 14 HIV patients whose viremia remained controlled for several yrs

after the interruption of prolonged cART initiated during primary infection

Pts standard cART available at time of tx (for some, all-NRTI tx)

HIV-1 RNA became undetectable in median of 3 months (0.5 to < 8 months)

Median cART duration: 36.5 months

PTCs lacked protective HLA-B alleles overrepresented in spontaneous HIV controllers (HICs)

Sáez-Cirio´A, et al. . Plos Pathogen. 2013;9: e1003211.

clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013

Long-Term Control of Viral Replication After Treatment During Primary Infection

Sáez-Cirio´A, et al. . Plos Pathogen. 2013;9: e1003211.