Joseph Eron, M.D., of University of North Carolina at Chapel Hill, presents "The State of the Art in HIV Cure Research – Hope or Hype: What Does It Mean for Patients" at AIDS Clinical Rounds

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AIDS CLINICAL ROUNDS

2. 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

3. 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.

4. 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

5. 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.

6. HIV-1 CAN BE CURED
The State of the Art in HIV Cure Research— Hope or Hype

7. CAN HIV-1 BE CURED?
Berlin Patient
Hütter G, et al. N Engl J Med. 2009;360:692-698.

8. 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.

9. Yukl et al PLoS Pathogens May 2013
Challenges in Detecting HIV Persistence during Potentially
Curative Interventions: A Study of The Berlin Patient

10. 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

11. 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.

12. “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-1RNA(copies/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

13. Specialized Studies to Assess Persistence of HIV-1
Infection in the Child.
Persaud D et al. N Engl J Med 2013;369:1828-1835

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

15. “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

16. 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
HIVDNA
(copies/106PBMC)
Post HSCT (days)
0 200 400 600 800 1000 1200 1400 1600
CD4(cells/mm3)
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
HIVDNA
(copies/106PBMC)
Post HSCT (days)
0 200 400 600 800 1000 1200 1400 1600
CD4(cells/mm3)
2.6 Years
Post-HSCT
(<0.04 copies/106)
HCST
100% Donor
Lymphocyte
Chimerism

17. 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

18. Analytical Treatment Interruption
Patient
Tacrolimus GVHD txt during ATI

19. Analytical Treatment Interruption
Patient

20. 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

21. 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.

22. 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

23. Reservoir Size in Treated AHI
Model including VL, CD4 and latent cell decay
Archin … Margolis, Perelson PNAS 2012

24. 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.

25. Fiebig I
Integrated HIV DNA at 24 weeks after ART
Not detected
Chronic HIV
Not detected
Fiebig III

26. Limited viral diversification in virus
from plasma and resting CD4 cells
5 years after treated acute HIV
infection.
Anderson et al J Virol 2011

27. 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.

28. 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

29. 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
101
102
103
104
105
106
0.0
0.5
1.0
1.5
2.0
2.5
3.0
1500 1750 2000
HIV-1RNA(copies/mL)
Diversity(%)
Start ART
2250
3.5107
Kearney M, et al. Unpublished data used with permission.

30. 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)
Frequency
(per106cells)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.

31. 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

32. 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.

33. Potential Interventions to Disrupt Latency
Richman DD, et al. Science. 2009;323:1304-1307.

34. “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.

35. 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-1gagRNAcopiesperwell
Archin NM, et al. Nature. 2012;487:482-485.

36. 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
N
H
H
N
NH
O
OH
Wei G, et al. CROI 2013. Abstract 376.

37. Slide 42
In Vitro Activation of HIV by HDAC Inhibitors
-11 -10 -9 -8 -7 -6 -5 -4
0
1×1005
2×1005
3×1005
Concentrations [Log10, M]
Luciferasesignal(RLU)
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

38. 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.

39. 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

40. 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.

41. Clones of Intact Non-induced Proviruses
Have Similar p24 Kinetics
Ho Y-C, et al. Cell 155, 540–551, October 24, 2013.

42. “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.

43. Spontaneous or Induced
Reversal of Latency
Stimulation and
recruitment of
immune effector
cells
Targeted antibody
or antibody-drug
conjugate delivery
YY
Elimination of
expressing
cells
No Infection
of CD4+T-
cells
Modified from Romas Geleziunas et al.
Strategies to reduce and/or
control HIV reservoirs

44. 0%
20%
40%
60%
80%
100%
120%
0 2 4 6 8
Healthy Donor 01
Healthy Donor 02
Healthy Donor 03
Elite Suppressor 01
Elite Suppressor 02
Elite Suppressor 04
HAART Patient 03
HAART Patient 05
HAART Patient 06
HAART Patient 12
HAART Patient 16
HAART Patient 17
HAART Patient 18
HAART Patient 19
ResidualinfectedCD4+Tcells(%)
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

45. 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
ResidualinfectedCD4+Tcells(%)
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

46. Pre-stimulation of CD8+ T Cells Enhanced
CTL Responses
Shan et al Immunity 2012

47. 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

48. 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

49. 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

51. 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

52. 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

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

54. 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
Log10HIVRNAcopiesper
105CD4orTotalThymocytes
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*

55. 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.

56. 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)

57. 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

58. 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

59. Thanks to all the patients
participating in cure research!

60. “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.

61. 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.