Upload
duonglien
View
215
Download
1
Embed Size (px)
Citation preview
Steven G. Deeks, MDProfessor of Medicine
University of California San FranciscoSan Francisco, California
HIV Cure and RemissionQuestions and a Few Answers
San Antonio, Texas: August 21-23, 2017
Slide 2 of XXSlide 2 of 49
Financial Relationships With Commercial Entities
Dr Deeks has received research support from
Merck, ViiV Healthcare, and Gilead Sciences,
Inc. (Updated 08/17/17)
Slide 4 of 49
HIV Cure: Lots of questions and a few answers
• How much is there?
• How stable is the reservoir?
• Where does it reside?
• Can it be measured?
• How will we cure HIV?
–Gene therapy
–Shock and kill
–Early ART
–Remission
Slide 5 of 49
What do we know about the size and
stability of the “reservoir”?
Slide 6 of 49
0 5 10 15 20 25 30 350
1
2
3
4
5
6
7
836160
3625336348
3634936488
3654436661
Start Treatment
3635336166
Weeks Post Infection
Lo
g v
RN
A C
op
ies/m
l
Although ART reduces viremia > 6 to 7 log10 some virus
persists indefinitely (0.1-3 copies RNA/mL)Source of the viremia is not known but it is not from an actively
replicating population
10104
103
105 (spleen)106 (large bowel)
105 (small bowel)106-7 (LN)
10 (kidney)
The vast majority of HIV resides in the lymphoid organs, most of
it assumed to be in CD4+ T cells, but the macrophage-rich
tissues are understudied?
Courtesy of Tim Schacker
(HIV+ cells/gram tissue)
The “active” reservoir in
lymph nodes declines slowly
over many years and appears
to be correlated with the level
of lymphoid inflammation
(germinal centers)
Slide 9 of 49
Slide 9 of 49
What do we know about the types of
CD4+ T cells that harbor HIV during ART?
Slide 10 of 49
Modest enrichment of HIV has been reported in
certain CD4+ T cell subsets
• Activated/proliferating
–HLA-DR, PD-1, LAG-3, CTLA-4, TIGIT
• T follicular helper cells (nodes)
• Migrating: CCR6, ⍺4 β7
• Effector cells
1Chomont, Nat Med 09. 2Murray JV 14. 3Hatano JID 12. 4Cockerham PLoS ONE 14. 5Wang JID 14. 6Chun
JCI 05. 7Riddler (unpublished). 8Lewin (unpublished). 9Hatano JID 14. 10Frometin (unpublished)
HIV enriched (100 to 1000
fold) in CD32a-expressing
CD4+ T cells
Most (> 50%) of reservoir
may be in these cells, even
though they are rare (~1%
of CD4+ T cell population)
Slide 12 of 49
Slide 12 of 49
How does HIV persist indefinitely?
Slide 14 of 49
Up to 50% of infected
cell population
(blood) is clonal in
nature
Integration sites
enriched for genes
associated with cell
growth/cancer
Cell proliferation maintains the reservoir during ART
Slide 15 of 49
B cell follicles: a relative sanctuary (low CTL, low ART)
and may be a site for “cryptic” replication
Fukazawa et al., Nature Med 2015; Banga et al., Nature Med 2016; Leong et al., Nature Immunol 2016
Slide 16 of 49
Can the reservoir be measured?
Slide 17 of 49
HIV Reservoir
Vast majority of genomes are defective
• Reservoir: Population of
replication-competent
HIV that persists during
ART and ignites new
rounds of replication
when ART is stopped
• Rare, tissue-based, may
be impossible to directly
measure
Slide 19 of 49
• Cancer: rare tissue
based cells that are
similar to healthy cells
and hard to detect
• Sensitive tracers that
detect cancer (or HIV)
being developed
Slide 20 of 49
How will we cure HIV infection?
Slide 21 of 49
Viable pathways toward a durable remission/cure
• Gene and cell-based therapy
• Shock and kill
• Lock and block
• Early ART
• Remission
Slide 22 of 49
Viable pathways toward a durable remission/cureGene and cell-based therapy
• Proof of concept: Berlin Patient
• Allogeneic stem cell transplant: several “near-
cures”– Studies illustrate that very low levels of HIV (< 1000 virions) are
sufficient to ignite new systemic infection
• Multiple feasible pathways, including direct
enzymatic excision of provirus
• Will this ever be scalable on a global level and
safer than ART?
Slide 23 of 49
Viable pathways toward a durable remission/cure
Shock and kill
• Latency reversal is possible, but has not yet been associated with
reservoir reduction
• Approach requires that all or nearly all virus be eliminated, which
will be challenging if not possible
• May be an important adjuvant to other approaches
Slide 24 of 49
Viable pathways toward a durable remission/cure
Block and lock
Most provirus is
difficult to reactivate
ex vivo
Permanent latency
may be inducible by
inhibiting tat or
several host
pathways, including
mTOR
Slide 25 of 49
Early ART
Can we cure HIV by starting ART
before the reservoir is fully
established?
Slide 26 of 49
At about the time
HIV RNA becomes
detectable, the
reservoir size
begins to increase
dramatically, with an
apparent 100-fold
increase over the
next two weeks
Reservoir largely
established by week
4 of infection
Slide 27 of 49
Very early ART reduces the reservoir but is not curative
N=8; ART in Fiebig I for
>96 weeks; VL<50 c/ml;
CD4>400 cells/ul
Ananworanich J et al., CROI 2017, Seattle, WA
ART (PrEP) during “Fiebig 0” Stage
Henrich T et al., IAS 2017, Paris, France
Lack of Detectable HIV DNA in a PrEP Study Participant:
Treatment Interruption
Henrich T et al., IAS 2017, Paris, France
Slide 30 of 49
• 20 adults (and one child) who started therapy early
(but not in “hyperacute” stage), remained on
therapy for years, and had no rebound after
stopping therapy
• Low reservoir size, low T cell activation and strong
immune responses
Slide 31 of 42
African child with durable remission post-ART
• Pre-ART (Infant)
– High viral load (> 750,000)
– Received ART for 40 weeks
– Controlled interruption (CHER)
– Lost to follow-up
• Post-ART (Age 9)
– Sustained virus control (> 8.5 years)
– Normal CD4+ T cell count,
– Weak antibody test (negative ELISA),
– Low HIV DNA (2.2 copies/million PBMCs)
– No protective HLA alleles, low T cell activation
Violari A et al., IAS 2017, Paris, France
Slide 32 of 42
DNA prime/rVSV boost among those treated during
early HIV infection (n=30): Many (~25%) in each arm
maintained virus control (< 400) during ATI
Fauci A et al., IAS 2017, Paris, France
Slide 33 of 49
HIV Remission
Can an HIV remission be routinely
achieved therapeutically?
Slide 34 of 49
All models of durable SIV/HIV remission suggest
that durable control of established infection will
require (1) low disease burden, (2) low
inflammation and (3) sustained T cell responses
that are primed, reside in tissues, and target
susceptible epitopes
These same attributes apply to cancer
immunotherapy
Slide 36 of 49
Immunotherapy for HIV infectionTwo decades of largely failed approaches
• Weak immunogenicity
– Pre-existing immuno-dominant responses
– CTL escape
• Inflammation and counter-regulatory
immunosuppression
• High virus burden
• Immune-privileged tissue sanctuaries
Slide 37 of 49
Broadly neutralizing antibodies
blocked SIV replication (as
expected) and induced a
sustained host response (likely
CD8+ T cell mediated)
Durable virus control observed
post-ART in people given
combination bNAbs
(Nussenzweig, IAS 2017)
Slide 39 of 49
Vaccine (Ad26/MVA prime-
boost) alone had minimal effect
on reservoir
Vaccine + TLR7 agonist
reduces reservoir during ART
and controls SIV post-ART
Vesatolimod now being tested
in phase I/II clinical trials
Slide 40 of 49
α4β7 integrin expression
enables migration of T cells
to gut mucosa
SIV infected monkeys on
ART treated with anti-α4β7
integrin antibody controlled
SIV post-ART
Effect mediated by NK cells
Slide 41 of 49
Cancer immunotherapy is reshaping a fatal and progressive
disease much as ART reshaped HIVMost therapies aim to enhance capacity of CD8+ T cells to recognize and
clear rare tissue-based cells that reside in inflamed tissues
• Upregulation of
checkpoint blockers (PD-
1, CTLA-4)
• Immunosuppressive
cytokines (TGF-β, IL-10,
IDO)
• Immunosuppressive
immune cells (T-regs,
MDSCs)
Slide 42 of 49
HIV Remission
Immune stimulation
Vaccines
bNAbs
Adjuvants
TLR agonists
Immune-modifying
ICBs
Anti-inflammatory Rx
Sanctuary Disruption
CD20 antibody
Cytokines
Low Reservoir
Early ART
bNAbs
LRAs
Slide 46 of 49
State of the ART: 2017
• Location, size and stability of reservoir remain to be characterized
– Measuring total body replication-competent reservoir not possible
– Cellular reservoirs now being explored
• Mechanisms for persistence known: latency, poor CTL, cell
proliferation
• The reservoir can be reduced with early ART and cell therapy but
not with anything scalable
• It is possible to reverse latency (shock) but the impact on the
reservoir is negligible and most approaches are toxic
• Therapeutic vaccines work in monkeys and perhaps humans
• Combination approaches will be needed and are now moving into
the clinic (era of “experimental medicine”)
Slide 50
•Use the microphones or Q-cards for questions
• If you are participating via the live webcast, please email your questions to [email protected]
Question and Answer Period