Nicolas Chomont University of Montreal Richard 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 ID: 364158
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HIV Cure Research Training CurriculumNicolas Chomont, University of MontrealRichard Jefferys, Treatment Action GroupThe 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 ResearchSlide2
Basic science: Laboratory studies that aim to further understanding of the mechanisms involved in phenomena e.g. the mechanisms of HIV persistenceTranslational research: Research that aims to translate knowledge gained from basic science into the clinic (sometimes referred to as “bench-to-bedside”)
DefinitionsSlide3
From Han et al, Nat Rev, 2007
HIV life cycleSlide4
Limit of detection
Antiretroviral drugs (HAART) are capable of suppressing HIV, even to undetectable levels
Circulating virus
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
HIVSlide5
HIV
persists
during
ARTSlide6
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?Slide7
Where
is
the HIV
reservoir
?
From http://
textbookofbacteriology.netSlide8
HIV
latency
From
Siliciano
et al. Cold
Spring
Harb
Perspect Med 2011 Slide9
IL-2
IFN-
g
Survival
Apoptosis
Self renewal
A
ctivation
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
Transitional
memory
Effector
memory
Terminally differentiated
Ag
“Stem cell” memory
CD4
T
cellsSlide10
HIV persists in central, transitional and effector memory CD4 T cellsChomont et al. Nat Med 2009
Cont
ribution of CD4
T
cells
to the HIV
reservoirSlide11
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?Slide12
« Size » of the HIV
reservoir
Ho et al.
Cell
2013
The « real
reservoir
» ?Slide13
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 DNAAmong 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
sizeSlide14
Minimal decay of the HIV reservoir
HIV
persistence
Siliciano
et al. Nat Med 2003Slide15
Half
life of the HIV
reservoir
Siliciano
et al. Nat Med 2003Slide16
Reservoir
established
rapidly
after
infectionSlide17
Early
ART
restricts
the size of the HIV
reservoir
(RV254)
Very early ART (<2 weeks after infection) dramatically reduces the size of the HIV reservoirSlide18
Absolute CD4 count
CD4 count (cells/µl)
Integrated HIV DNA copies per 10
6
CD4 T cells
= -0.38
p = 0.03
200
700
1200
1
10
100
1000
10000
CD4/CD8
ratio
CD4/CD8 ratio
> 1
< 1
p < 0.0001
1
10
100
1000
10000
Higher
CD4 count,
smaller
reservoirSlide19
Two strategies to eliminate the reservoir: Reactivation of HIV replication from its latent reservoir
Interfering with the immunological mechanisms that contribute to HIV persistence
HAART
HAART
HAART
HAART
HAART
HAART
HIV-induced cell death
Uninfected cells
Cytokines, chemical compounds…
T cell survival
Proliferation
Antibodies, cytokines, gene therapy, chemotherapy
Translating
basic science
into
interventionsSlide20
HistonesCellular proteins that encase genes and prevent their transcriptionHIV genes can be freed form histone entrapment by drugs called histone deacetylase (HDAC) inhibitorsHDAC 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
latencySlide21
Targeting
molecular
mechanisms
of HIV
latencySlide22
Targeting
molecular
mechanisms
of HIV
latencySlide23
Richman et al. Science 2009PKC agonists
:
Prostratin
B
ryostatin
Gamma-c Cytokines:
IL-7
IL-15
Bromodomain
inhibitorsJQ1I-BETHDAC inhibitorsSaha (vorinostat)PanobinostatRomidepsin
Targeting molecular mechanisms
of HIV latencySlide24
T-cell activation
PKC
Cytokines
HDACi
other
Spina
et al.,
Plos
Pathogens
2013 Dec;9(12):e1003834
Targeting
molecular
mechanisms
of HIV
latencySlide25
CD4 T cells respond to signals from their environment via receptors on the cell surfaceThe 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 stateThese 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
latencySlide26
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)Slide27
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
reservoirSlide28
Chen L, Nat Rev Imm. 2013
PD-1 and moreSlide29
R. Fromentin, Means +/-SD from 5 ART subjectsCD4 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
regulatorsSlide30
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.
FromentinSlide31
The negative regulators PD-1, LAG-3 and TIGIT identify CD4 T cells harboring integrated HIV DNABlocking these receptors may revert HIV latency and possibly also enhance HIV-specific T cell responsesA clinical trial of an antibody to PD-L1 is ongoing (ACTG A5326)
PD-1 blockade may also be studied
Targeting
immunological
mechanisms
of HIV
latencySlide32
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 2014Slide33
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
latencySlide34
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
researchSlide35
CRCHUM
Rémi
Fromentin
VGTI Florida
Claire
Vandergeeten
Francesco
Procopio
Mariam
LawaniWendy BakemanAmanda McNultyJessica BrehmDeanna KulpaRafick-Pierre Sékaly MHRPJintanat AnanworanichJerome KimMerlin RobbNelson MichaelInstitut PasteurAsier-Saez-Cirion
MerckDaria Hazuda
Mike MillerRichard Barnard
UCSF
Hiroyu HatanoMa Somsouk
Peter HuntElisabeth Sinclair
Rick HechtRebecca HohLorrie Epling
Mike McCuneSteven Deeks
Westmead InstituteSarah Palmer
Eunok Lee McGillJean-Pierre
RoutyVRC
Danny DouekEli Boritz
Acknowledgments
UNC
Karine
Dubé
AVAC
Jessica HandibodeSlide36
Collaborators
The study participants!