1. Toward A Cure for HIV Plenary Lunch
Keynote Dr. Sharon Lewin
Head, Department
of Infectious Diseases
Alfred Hospital
and Monash University

2. Finding a cure for HIV: the need for science, advocacy and collaboration Sharon R Lewin Director, Infectious Disease Unit, Alfred Hospital Professor, Department of Medicine, Monash University Co-head, Centre for Virology, Burnet Institute, Melbourne, Australia US Conference on AIDS, Las Vegas, October 1st., 2012
Thank you Dr Whitescarver for the kind introduction and a special thank you to Paul Kuwata for inviting me to address to you today – not only a pivotal time in the HIV/AIDS epidemic but also a very exciting time when scientists, clinician and communities should no longer be hesitant to say the words “HIV Cure” and a time where “finding a cure” is rapidly becoming a major priority on the research agenda

3. Over the past months, we have all be tremendously excited about the growing momentum and commitment to end AIDS or at least see an AIDS free generation in you and my life time

4. The end of AIDS? seek, test and treat prevention cure
Some think that the end of AIDS might be possible by treatment alone. The results of HPTN 052 have unequivocally shown us that treatment significantly reduces transmission – so finding, testing and treating everyone could potentially work. IT’s a very expensive option but is an approach we must continue to advocate for. Prevention of any new infections may also one day be achievable with the demonstrated success of PREP, microbicides and hopefully one day an effective vaccine. However, the third and critical component of ever seeing an end not just to AIDS, but and end to HIV, is to find a cure. Even if we had an effective vaccine tomorrow, there are 33 million infected with HIV, all who need to reliably access and adhere life long treatment

5. Why we need a cure for HIV
Life expectancy remains reduced and ongoing morbidity on cART
For every 2 new patients who initiate cART there are 5 new infections
Globally, only 60% of patients who need cART are being treated
Funding lifelong cART for all who need it is unlikely to be sustainable

6. Outline What are the major barriers to cure?
What type of cure might be achieved?
What is being tested in clinical trials?
Current and future challenges in HIV cure research

7. what are the major barriers to cure?

8. Virus persists in all patients on cART
Tissue
Cell associated HIV DNA
Cell associated HIV RNA
Blood
Cell associated HIV RNA
Infectious virus (IUPM)
Cell associated HIV DNA
HIV RNA 50
Plasma single copy assay 1 1
Years on cART
Chun et al., Nature 1997; 387: 183; Lewin et al., J Virol 1999; 73:6099; Palmer et al., Proc Natl Acad Sci U S A.
2008;105:3879; Chun et al., J Infect Dis 1997;195:1762; Yukl J Infect Dis 2010; 8 8

9. Barriers to cure Latently infected T-cells Residual viral replication
Anatomical reservoirs

10. HIV latency and infection of resting T-cells
cART
Activated CD4+ T-cell
Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med 2006; 203:865; Saleh et al., Blood 2007;
110:416; Marini et al., J Immunol 2008; 181: ; Bosque and Planelle, Blood 2009; 113:58;
Cameron et al., Proc Natl Acad Sci 2010; 107(39):16934
Resting CD4+ T-cell
HIV latency

11. Latently infected T-cells
cART

12. Residual replication
cART

13. Anatomical reservoirs

14. What type of cure might be achieved?

15. HIV eradication: cure or remission
Infectious Diseases model
Cancer model
Elimination of all HIV-infected cells
Long term health in absence of cART
HIV RNA < 1 copy/ml
HIV RNA < 50 copies/ml
Sterilising cure
Functional cure

16. Timothy Brown and Matt Sharp

17. Sterilising cure: transplantation of “HIV resistant” bone marrow
scBMT
(X2)
Donor
CCR5–
(DD32)
Chemotherapy (x4)
Total-body irradiation (x2)
“CCR5–”
off cART
no viral rebound
“sterilising cure”
cART
CCR5+
(WT)
HIV+
Leukemia (AML)

18. Sterilising cure: lessons learned
Bone marrow
transplantation
2nd bone marrow
transplantation
AML diagnosis
cART
cART
107
GI tract biopsy
CSF
Brain biopsy
106
105
Plasma RNA +/-
GI tract DNA +/-
? significance
HIV-1 RNA (copy/mL)
104
103
102
2007
2008
2012
Hutter et al., N Engl J Med, 2009; 360:692; Allers et al., Blood (10):2791; Yukl et al., International
Workshop on HIV and Hepatitis Resistance, Sitges, June 2012

19. Could allogeneic transplantation be enough?
BMT
CCR5+
(WT)
Reduced intensity irradiation (RISC)
HIV+
Lymphoma
(n=2)
CCR5+
(heterozygous)
cART
HIV DNA neg
HIV RNA neg
(2-4 yrs post Tx)
Henrich et al., XIXth IAC, Washington DC, July 2012

20. Functional cure: elite controllers
Strong HIV-specific T-cell responses
Enriched for “protective” HLA types
Long term effects
Loss of CD4 (7%)
Ongoing virus replication and evolution
Immune activation increased
Long term non-progressors
Elite
Controllers
VL<50c/ml
Hunt et al., J Infect Dis 2008 ;197:126; Hatano et al., J Virol 2009; 83: 329; Pereyra et al., J Infect Dis 2009; 200:984; HIV Controller Study, Science. 2010;330(6010): Soghoian DZ et al., Sci Transl Med 2012; 4(123):123ra25; Hersberger et al., Blood. 2011;117(14):

21. Functional cure: post cART controllers
CASCADE cohort; Europe and Aust; n=259 treated in acute infection and ceased cART
VISCONTI cohort
n=14, France
treated in acute infection
median time on ART =37 months;
median times since stopping ART = 80 months
“Unique” immunological profile
<5.5%
Hocqueloux et al., AIDS 2010; 2010;24(10):1598; Goujard et al., Antiviral Therapy 2012;17:1001;
Lodi et al., Arch Int Med 2012; 172(16):1252; Saez-Cirion et al., XIXth IAC, Washington DC, July 2012

22. What “cure” do PLWHA want?
No ART
Not infectious
Never get HIV again
Option 1 
Option 2
potentially
Option 3
Option 4
Highly desirable
Somewhat desirable
95% 5
41%
27%
24%
32%
19%
32%
Survey of Dutch PLWHA; N=458 (46% of respondents)
Verdult, F, IAS HIV Cure Workshop, Washington DC, July 20-21, 2012

23. Strategies to achieve a cure
Eliminate latently infected cells
Eliminate residual virus replication
Enhance HIV-specific immunity
Make cells “resistant” to HIV

24. current clinical trials: eliminating latently infected cells

25. Eliminate latently infected T-cells: activate latent HIV
cART
Activated CD4+ T-cell
Resting CD4+ T-cell

26. Activating latent HIV
The Economist, July 17, 2011

27. Activating latent HIV: in vitro
Histone deacetylase (HDAC) inhibitors1, 2
Cytokines
IL-73,4
IL-155
Anti-alcohol agent
Disulfuram6
Methylation inhibitors
5-aza-dC7
Immune modulation
Anti PD1
NF-kB activators
Prostratin, PMA, TNF4
Akt/HEXIM-1 modulators
HMBA8
Histone Methyltransferase inhibitors (HMTI)9
Chaetocin, BIX-01294
Other
Quinolines10
Combination enhances potency4,9,11
1Contreras, J Biol Chem. 2009;284(11):6782-9; 2Wightman., Immunol Cell Biol 2012; 3Wang, J Clin Invest 2005;
115:128; 4Saleh, Retrovirology 2011;8:80; 5Chomont, 6th IAS Rome 2011; 6Xing, J Virol; 2011;85(12):6060-4;
7Friedman, J Virol; :9078-8; 8Contreras PLoS Pathog (10): ; ; 9Bouchat, AIDS 2012;
10Xing et al., J Antimicrob Chemother. 2012;67(2): ; 11Reuse et al., PLos One 2009;4:e6093

28. Activating latent HIV: HDACi vorinostat*
cART
Vorinostat 400 mg/day 14 84
Australia; n=20
Rectal biopsy
day
cART>3 years
HIV RNA<50 c/ml
CD4>500 cells/ml 7 1 3
cART
200mg
400mg 2 4 3
US; n = up to 20
Leukapharesis (post dose as per PK) *
visit
cART > 6 months
HIV RNA < 50 c/ml
CD4 > 300 cells/ml
In vitro response to vorinostat 1 5 PK
Archin et al., Nature 2012; 487: 482

29. Vorinostat turns HIV genes “on” in vivo
Baseline cART
Vorinostat 400 mg
800
600
400
200 60 40 20
Pt 1
Pt 2
Pt 3
Pt 4
Pt 5
Pt 6
Relative HIV-1 gag copies
100
Pt 7
Pt 8
Cell associated RNA quantified in resting CD4+ T-cells (mean of replicates)
Archin et al., Nature 2012; 487: 482

30. Trials of other latency “activating” agents
Design
PI (location)
Status
HDACi
Vorinostat
14 days
400 mg/day
Lewin (Australia)
Fully enrolled
Panobinostat
3 x /week x4
Ostergard (Denmark)
Enrolling
Rhomedepsin
Single dose
ACTG (US)
In discussion
Cytokine
IL-7
3 doses +intensification
Katlama (Europe)
Other
Disulfiram
500 mg/day
Deeks (US)
Ongoing
3 days
dose escalation
Elliot/Lewin (Australia)
Submitted
Anti-PD-1

31. Will latently infected T-cells die post activation?
cART
Activated CD4+ T-cell
Shan et al., Immunity 2012; 36:1-11 +
Immune clearance ?
Resting CD4+ T-cell

32. Latently infected cells are rare

33. current clinical trials: eliminating virus replication

34. Eliminating viral replication: no effect of treatment intensification
Dinoso et al., Proc Natl Acad Sci U S A, (23): 9403; McMahon et al., Clin Infect Dis, : 912; Ghandi et al., J Infect Dis :293; Buzon et al., Nat Med, : 460; Ghandi et al., Plos Med 2011;7 Yukl et al., AIDS 2010;16:2451; Hatano et al., J Infect Dis 2011; 203:960; Gutierrez, Plos One 2011:12:e27864
T20
LPV/r
ATV/r
Raltegravir (x5)
Maraviroc (x3)
HIV RNA
HIV DNA 50 1 1
Years on cART
intensification 34 34

35. Eliminating viral replication: the need to go beyond cART
Reduce immune activation1
Mesalamine (UCSF)
Rifaximin (ACTG)
ACE inhibitors (lisinopril; UCSF/amfAR)
Methotrexate (ACTG)
Enhance tissue/cell delivery
Nanoparticles2
Pro-drugs eg., GS-73403
Target cells of the myeloid lineage
1Clinical trials.gov; 2Kovochich et al., Plos One 2011; 6: e18270; 3 Ruane et al., 19th CROI Seattle #103

36. current clinical trials: making cells resistant to HIV

37. Nucleases chop up DNA: eliminate CCR5 expression
Naldini et al., Nature Genetics 2011; 12:301; Holt et al., Nature Biotechnol 2010;28(8):839-47; Lalezari et al.,
18th CROI, Boston, Feb 2011; Tebas et al., 18th CROI, Boston, Feb 2011 abstract 165

38. Gene therapy to eliminate CCR5
Inclusion criteria n
NCT
(PI Tang, Sangamo; 5 cohorts)
Dose escalation
3 x 3
cART failure 4
CCR5D32 hetero
20*
NCT
(PI Tebas, Sangamo; 3 cohorts) 6
Stable cART 6*
Poor CD4 recovery
NCT
(PI Tang, Sangamo)
No cART 30
* Treatment interruption
Lalezari et al., 18th
CROI, Boston, 2011

39. current and future challenges in HIV cure research

40. Scientific challenges
Multiple barriers to eradication means a combination approach will be likely
Standardised, non-invasive assays to quantify viral reservoirs in vivo for multi-site clinical trials
Drug development to increase specificity for latently infected cells, enhance tissue delivery and reduce toxicities
Better understanding of the immune system in controlling low level viremia and latent infection

41. Ethical considerations
What are acceptable risks and toxicities of interventions in a population doing well on stable cART?
What marker(s) of viral persistence will justify treatment interruption as a clinical endpoint in subsequent clinical trials?
Expectations of study participants in early “proof of concept” studies. Community literacy and engagement is critical
Universal access to cART must remain a top priority

42. science, collaboration and advocacy

43. Funding cure research

44. Towards an HIV Cure: a global scientific strategy launched July 2012

45. An integrated strategy
Int’l scientific collaborations
Interaction between
Basic + Clinical Science
Data exchange platforms between pilot studies
New concepts,
new generation
Cross-talk with other scientific disciplines
Cooperation
public + privates
sectors
Community engagement
Funding

46. We need a cure that is scalable, deliverable and cheap

47. Acknowledgements National Association of People living With AIDS
Department of Medicine, Monash University
Paul Cameron
Suha Saleh
Ajantha Solomon
Fiona Wightman
Miranda Smith
Pushparaj Velaydham
Gabriela Khoury
Vanessa Evans
Nitasha Kumar
Jenny Anderson
Hao Lu
The Alfred
Julian Elliott
Jennifer Hoy
Janine Roney
James McMahon
National Association of People living With AIDS
Jo Watson
Bill Whittaker
Peter Macallum Institute
Miles Prince
Ricky Johnston
Others
Steve Deeks
Christine Katlama
Brigitte Autran
Christine Rouzioux
Dan Kuritzes
Javier Picado Martinez