Shirin HeidariInternational AIDS Society

EC Think Tank meeting27-28 October 2010

Luxemburg

Can HIV be cured? (how about long term Drug free remission?)

HAART can control HIV, cannot eradicate it

Cost

Risk for CVD and cancer

with age

Transmission Resistance

Adherence

Adverse effect

Life long treatment

High Active Antiretroviral

Therapy (HAART)

Therapeutic cure and prophylactic vaccines are rational ways to tackle the epidemic.

Source: Towards Universal Access, Progress Report September 2010

Growing need

Estimated number of people in need of ART 14,6 million (from 10,1 million )For each person put on HAART = 2-3 person newly infected

1996/1997

>3 years of HAART to eradicate HIV?

Courtesy of Nicholas Chomont

Courtesy of Nicholas Chomont

Ongoing viral replication occurs in subjects on suppressive HAART (TW Chun, JCI ; N Tobin, J Virol 2005).

HIV integrate in long lived resting memory T cells and persist despite suppressive HAART(TW Chun, Nat. Med 1995, D Finzi, Science ; TW Chun, PNAS 1997).

Reservoir cells, like other memory T cells, divide very slowly to maintain the memory of the immune system (A. Bosque and V. Planelles)

Courtesy of Nicholas Chomont

The Berlin Patient 2007/2008Gero Hutter

Proof Of ConceptHealthy donor

with CCR5 mutation

HIV positive recipient

Stem cells without CCR5

HIV patient functionally cured by bone marrow transplant

Objectives:• Present state of the art research on the control of HIV reservoirs• Accelerate research towards a potential HIV cure• Highlight the importance of basic science to the HIV response • Re-engage the broader HIV community in basic science• Strategize to accelerate the translation of findings into clinical practice• Provide a networking opportunity for HIV scientists to share ideas and debate with peers

2010 IAS Workshop Towards a Cure: HIV Reservoirs and strategies to control them

199 attendees

65 Scholarship recipients

62 abstracts presented

9 invited speakersClinical Implications of HIV Persistence

HIV Reservoirs and Sanctuary Sites

HIV Reservoirs and Mucosal Immune Restoration during HAART

Mechanisms of Persistence in HIV Infected Individuals

The role of the immune system in HIV persistence

The role of host factors in HIV persistence

Potential therapeutic interventions and how to evaluate them

Eradication versus remission: is eradication possible?

IAS/ANRS Young Investigator Award on HIV ReservoirsReview in Science: HIV Persistence and the Prospect of Long-Term Drug-Free Remissions for HIV-Infected Individuals (Trono et al.)

Abstract and meeting report Supplement in Journal of the International AIDS Society

IAS workshop Towards a CureAIDS2010 Vienna

Brief Overview of ongoing research on HIV reservoirs and mechanisms

of persistence

Eradicating cure Functional cureElimination of all HIV-

infected cellsLong term viral

suppression in absence of HAART

HIV RNA < 1 copy/ml HIV RNA < 50 copies/ml

Cure Remission

Inspired by Sharon Lewin, AIDS 2010 Plenary « Strategies for a Cure »

How to control /reduce HIV reservoirs?

Intensification of HAART (+/- other interventions)

Early initiation of HAART (limit viral reservoirs)

Improved Drugs (penetrating anatomical compartments)

Treatment intensification does not reduce residual HIV-1 viremia in patients on HAART (Dinoso

et al PNAS 2009)

HIV-1 replication and immune dynamics are affected by Raltegravir intensification of HAART-suppressed subjects (Buzon et al Nat Med 2010)

HAART intensification (plus raltegravir and maraviroc) in combination with other interventions (HIV vaccine (DNA+rAd5 or Immunomodulator IL7): Eramune 1& 2 (Katlama/Autran)

HAART initiation during acute infection limit the frequency of latently infected cells and

preserve HIV specific memory CD4 T cells (Trono et al, Science 2010, Chun et al PNAS 2001)

A high HIV DNA level in PBMCs at antiretroviral treatment interruption predicts a shorter

time to treatment resumption, independently of the CD4 nadir (Pikett et al J Med Virol. 2010 (ANRS 116 SALTO

Study Group))

Courtesy of Nicholas Chomont

IL-7 reactivates latent HIV in vitro, also improves HIV-specific immune response but also

promotes homeostatic proliferation of HIV latently infected cells (Trono et al, Science)

HDAC inhibitors & chromatin modifiers: may reactivate HIV production thereby reducing the

pool of latently infected cells (Torno et al, Science)

Gar1041 (an experimental leukemia drug) in combination with HAART transiently reduces

the proviral DNA reservoir in SIVmac251-infected macaques, (Savarino, Abstract; the IAS HIV Reservoirs

Workshop 2010) First encouraging results (Italy) in laboratory and primate model for potential long term remission

Purging the Reservoir by Disrupting the PD-1 negative pathway during HAART? (Da Fonseca,

Abstract: the IAS HIV Reservoirs Workshop 2010)

How to control /reduce HIV reservoirs?Reactivation of HIV replication from latent reservoirs: ”Shock and Kill”

Interfering with immunological mechanism that contribute to HIV persistence

Other therapeutic interventions (Gene/Mol therapy, ther. vaccine)

Reservoir are maintained by Immune regulators such as PD-1 and Ki67 (Da Fonseca, Abstract: the IAS HIV Reservoirs Workshop 2010, Chomont Nat Med 2009)

Eramune 02 – Therapeutic Vaccine + Integrase Inhibitor + anti-CCR5 (Clinical Trial NCT00976404)

A model for an immune control of the HIV Reservoirs in HLA-B27/57+ LTNPs, (Descours et al, submitted)

Targeting pathways downstream of homeostatic proliferation (Chomont et al. Nat Med 2009).

Zinc-finger nucleases to disrupt CCR5 in progenitor stem cells - control of HIV in mice (Holt & Cannon: Nature Biotechnology 2010)

How to control /reduce HIV reservoirs?

Courtesy of Nicholas Chomont

While we are searching for a cure:Keep patients ready by:

Universal Access

Early Treatment (Limiting the reservoirs and preserve immune system)

Invest in research:Better understanding of biological mechanism and role of the immune system in establishing reservoirs and persistence

Better tools and models In vitro and in vivo models

More precise assays and sensitive techniques

Drug development: increased specificity for latently infected cells

Translational Research

Inspired from Sharon Lewin, AIDS 2010 Plenary « Strategies for a Cure »

Global Scientific Strategy Towards an HIV Cure

IAS to coordinate and support the creation of an international multidisciplinary scientific advisory group on HIV Reservoirs to develop a Global Scientific Strategy « Towards an HIV Cure »

A Global Scientific Consortium « Towards an (functional) HIV Cure » ?

The strategic role of the EU

Global Scientific Strategy « Towards a (functional) HIV Cure »?

Invest in research on HIV reservoirsInclude a specific call in FP7 (Coordinated Action?)

International HIV Reservoir Research Consortium?

AcknowledgementsInternational AIDS Society, Geneva

Marie-Capucine Penicaud

Tamara Torri

Anthony Flynn

With courtesy of members of IAS programme committee Towards An HIV Cure who shared their slides:

Françoise Barré-Sinousi, Institute Pasteur, Paris, France

Nicolas Chomont, Vaccine and Gene Therapy Institute Florida, USA

Tae-Wook Chun, National Institutes of Health, USA

Alain Lafeuillade, Department of Infectious Diseases, General Hospital, Toulon, France

Sharon Lewin, Burnet Institute, Melbourne, Australia