hiv cure and remission questions and a few answers · pdf file · 2017-08-28hiv...

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

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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JCI 05. 7Riddler (unpublished). 8Lewin (unpublished). 9Hatano JID 14. 10Frometin (unpublished)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

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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

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• 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

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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


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


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

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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

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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?

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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)

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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)

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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

mailto:[email protected]

hiv cure and remission questions and a few answers · pdf file · 2017-08-28hiv...

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