hiv cure research training curriculum nicolas chomont, university of montreal richard jefferys,...
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HIV Cure Research Training CurriculumNicolas Chomont, University of MontrealRichard Jefferys, Treatment Action Group
The HIV CURE training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field.
CONCEPTS IN BASIC SCIENCE AND TRANSLATIONAL RESEARCH
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• Basic science: Laboratory studies that aim to further understanding of the mechanisms involved in phenomena e.g. the mechanisms of HIV persistence
• Translational research: Research that aims to translate knowledge gained from basic science into the clinic (sometimes referred to as “bench-to-bedside”)
Definitions
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From Han et al, Nat Rev, 2007
HIV life cycle
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Limit of detection
Antiretroviral drugs (HAART) are capable of suppressing HIV, even to undetectable
levelsCi
rcul
ating
viru
s
Time
START STOP
HAART
However, the virus rebounds after
cessation of therapy
HIV hides in reservoir that are not sensitive to current therapies
HIV infection is characterized by high levels of circulating viruses
in the blood
Current anti-HIV drugs do not eradicate HIV
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HIV persists during ART
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• Proliferation: Reservoir cells, like other memory T cells, divide very slowly to maintain the memory of the immune system.
• T cell survival: Reservoir cells are memory T cells. These cells, which are generated after infection or vaccination, keep the memory of the immune system for decades.
Ongoing viral replication
Active reservoir
Latent reservoir
How does HIV persist during ART?
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Where is the HIV reservoir?
From http://textbookofbacteriology.net
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HIV latency
From Siliciano et al. Cold Spring Harb Perspect Med 2011
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IL-2IFN-g
SurvivalApoptosis
Self renewalActivation
Sallusto et al. Nature 1999 ; Riou et al. J Exp Med. 2007 ; Ahmed et al. Nat. Rev Immunol 2009 ; Gattinoni et al. Nat Med 2011 ; Farber et al. Nat. Rev Immunol 2014
Naïve Central memory
Transitionalmemory
Effectormemory
Terminally differentiated
Ag
“Stem cell” memory
CD4 T cells
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HIV persists in central, transitional and effector memory CD4 T cells
Chomont et al. Nat Med 2009
Contribution of CD4 T cells to the HIV reservoir
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• At the anatomical level: Potential “hiding places”• Brain• Lymph nodes (inc. B cell follicles)• Peripheral blood• Gut• Bone marrow
Adapted from A. Fauci
Where does HIV persist during ART?
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« Size » of the HIV reservoir
Ho et al. Cell 2013
The « real reservoir » ?
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The frequency of cells harboring HIV integrated DNA is 10-1000 per 106 CD4 T cells 0.1-0.001% of CD4 T cells contain HIV integrated DNA
Among these cells, 0.1-1% are able to produce infectious viral particles upon stimulation (Finzi, Siliciano Nat. Med. 1999)
=> 0.001-0.000001% of CD4 T cells harbor infectious HIV
The total number of CD4 T cells in humans is estimated to 200X109
(Gasunov and De Boer, Trends in Immunology, 2007)
This calculation does not include additional reservoirs such as tissue macrophages
The total number of « reservoir CD4 T cells » in suppressed individuals may be 100,000 -10,000,000
Estimated HIV reservoir size
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Minimal decay of the HIV reservoir
HIV persistence
Siliciano et al. Nat Med 2003
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Half life of the HIV reservoir
Siliciano et al. Nat Med 2003
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Reservoir established rapidly after infection
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Early ART restricts the size of the HIV reservoir (RV254)
Very early ART (<2 weeks after infection) dramatically reduces the size of the HIV reservoir
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Absolute CD4 count
CD4 count (cells/µl)
Inte
grat
ed H
IV D
NA
copi
es
per 1
06 CD
4 T
cells
= -0.38p = 0.03
200 700 12001
10
100
1000
10000
CD4/CD8 ratio
CD4/CD8 ratio
> 1< 1
p < 0.0001
1
10
100
1000
10000
Higher CD4 count, smaller reservoir
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Two strategies to eliminate the reservoir:
• Reactivation of HIV replication from its latent reservoir
• Interfering with the immunological mechanisms that contribute to HIV persistence
HIV-induced cell death
Uninfected cells
Cytokines, chemical compounds…
T cell survival ProliferationAntibodies, cytokines,
gene therapy, chemotherapy
Translating basic science into interventions
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• Histones• Cellular proteins that encase genes and prevent their
transcription• HIV genes can be freed form histone entrapment by
drugs called histone deacetylase (HDAC) inhibitors• HDAC inhibitors promote production of HIV RNA (and
maybe proteins) by latently infected cells • Vorinostat, panobinostat and romidepsin being evaluated
in clinical trials
Targeting molecular mechanisms of HIV latency
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Targeting molecular mechanisms of HIV latency
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Targeting molecular mechanisms of HIV latency
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Richman et al. Science 2009
PKC agonists: ProstratinBryostatin
Gamma-c Cytokines:IL-7IL-15
Bromodomain inhibitorsJQ1I-BET
HDAC inhibitorsSaha (vorinostat)PanobinostatRomidepsin
Targeting molecular mechanisms of HIV latency
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T-cell activation PKC Cytokines HDACi other
Spina et al., Plos Pathogens 2013 Dec;9(12):e1003834
Targeting molecular mechanisms of HIV latency
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• CD4 T cells respond to signals from their environment via receptors on the cell surface
• The receptors expressed on a CD4 T cell also fluctuate in response to signaling from the environment
• HIV latency in CD4 T cells is associated with the expression of receptors that are involved in maintaining the CD4 T cell in a resting state
• These receptors are referred to as “negative regulators” or “immune checkpoints” as they are also involved in preventing immune reactions to self (autoimmunity)
Targeting molecular mechanisms of HIV latency
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PD-1
• Negatively regulates T cell responses (Freeman J Exp Med 2000, Wei PNAS 2013)
• Two known ligands: PD-L1 and PD-L2, mostly expressed by myeloid cells (Freeman J Exp Med 2000, Latchman Nat Immunol 2001)
• Blocking PD-1 interaction with its ligands restores HIV specific T cell functions (Day Nature 2006, Trautmann Nat Med 2006, Porichis Blood 2011)
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r = 0.61p < 0.0001
The frequency of cells harboring integrated HIV DNA correlates with PD-1 expression
Hatano et al. JID 2013
PD-1 and the HIV reservoir
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Chen L, Nat Rev Imm. 2013
PD-1 and more
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R. Fromentin, Means +/-SD from 5 ART subjects
CD4 T cells expressing multiple negative regulators are highly enriched for integrated HIV DNA
CD4 Memory CD4
0 1 2 3 Number of negative regulators expressed
Expression of multiple negative regulators
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Blocking PD-1 in vitro induces a modest but significant increase in viral production in latently infected CD4 T cells
Reactivation of the latent HIV reservoir
R. Fromentin
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• The negative regulators PD-1, LAG-3 and TIGIT identify CD4 T cells harboring integrated HIV DNA
• Blocking these receptors may revert HIV latency and possibly also enhance HIV-specific T cell responses
• A clinical trial of an antibody to PD-L1 is ongoing (ACTG A5326)
• PD-1 blockade may also be studied
Targeting immunological mechanisms of HIV latency
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• Manipulating the tight regulation of the immune system has to be carefully evaluated (autoimmunity?)
• So far, clinical studies with ICBs have been performed in patients with cancer
• Possible additional side effects in HIV-infected individuals?
Risk consideration of immune checkpoint blockers
Gelao et al. Toxins 2014
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• Other approaches with the potential to interfere with the proliferation and/or survival of latently infected CD4 T cells also being explored (e.g. mTOR inhibitors, auranofin)
Targeting immunological mechanisms of HIV latency
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• Basic research findings on molecular and immunological mechanisms of HIV persistence are being translated into clinical trials of possible interventions
• These are many other examples of translational research in the HIV cure field, trials of gene therapies, therapeutic vaccines and immune-based therapies also based on basic research discoveries
• Additional CUREiculum modules provide more information on all these approaches: http://www.avac.org/cureiculum
Translational research
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CRCHUMRémi Fromentin
VGTI FloridaClaire VandergeetenFrancesco ProcopioMariam LawaniWendy BakemanAmanda McNultyJessica BrehmDeanna KulpaRafick-Pierre Sékaly
MHRPJintanat AnanworanichJerome KimMerlin RobbNelson Michael
Institut PasteurAsier-Saez-Cirion
MerckDaria HazudaMike MillerRichard Barnard
UCSFHiroyu HatanoMa SomsoukPeter HuntElisabeth SinclairRick HechtRebecca HohLorrie EplingMike McCuneSteven Deeks
Westmead InstituteSarah PalmerEunok Lee
McGillJean-Pierre Routy
VRCDanny DouekEli Boritz
AcknowledgmentsUNCKarine Dubé
AVACJessica Handibode
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Collaborators
The study participants!