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Track A Rapporteur Team
Dr. Nilu Goonetilleke
Dr. Zabrina Brumme
Dr. Matthew Parsons
Dr. Mark Brockman
Dr. Jenniffer Maroa
Dr. Renee van der Sluis
A new era in our fight against HIV: the possibility of a world without AIDS
“Breathtaking advances in treatment and prevention allow us to
consider the possibility of a world without AIDS” - Anthony Fauci
“An HIV cure is possible”
- Jintanat Ananworanich
-“The AIDS free world that many of you have worked for so long to
build is just over the horizon”
– President Bill Clinton
Slide credit: Dr. Anthony Fauci
HIV latency, reservoirs and eradication: challenges and complexities
Deborah Persaud
Carine van Lint
Plasma viral rebound in
the “Mississippi Child”
after 27 months of
remission
-> provides definitive
proof of how early the
reservoir is seeded in HIV
Complex epigenetic and
non-epigenetic
mechanisms of viral
latency
Melissa
Churchill
Anatomical HIV
reservoirs may differ in
their relevance to the
pathogenesis of latency,
and their ability to be
safely eliminated
HIV latency, reservoirs and eradication: challenges and complexities
Sarah Palmer
- challenges in quantifying the latent
reservoir and assessing replication
competence
- novel, standardized methods are
urgently needed
Image credit: Sarah Palmer
Nicolas Chomont
Extraordinary heterogeneity of T cell
subsets in terms of:
-their contribution to the total reservoir
-their longevity of persistence
-their susceptibility to reactivation by
therapeutic approaches
Chomont et al. Nat Med 2009
Combination approach to sustained HIV remission
Early HAART
-> reduce seeding of the reservoir & “stack the deck” in favor of eradication
Combination “kick and kill”
-Reactivate reservoir with anti-latency agents
-Eliminate CCR5+ cells by gene therapy
-Boost humoral and T-cell immunity via vaccines/immunotherapies
Image: Ole Søgaard; quote: Anthony Fauci
Romidepsin treatment for latency reactivation: AIDS 2014 breakthrough
Ole Søgaard
pVL (copies/ml)
Phase I/II nonrandomized trial (N=6): HDAC inhibitor romidepsin safely activated
latently infected cells and induced transient quantifiable plasma viremia
Days post-infection
An alternative to “kick and kill”:
Latency maintenance via permanent silencing
Eric Verdin
shRNA library screen identified host
proteins/pathways that contribute to latency
modulation
mTOR pathway inhibitors blocked reactivation
from viral latency
Hiromi Imamichi
Persistent release of HIV transcripts from infected cells
harboring defective proviruses during HAART
-> driver of chronic immune activation?
-> if so, need interventions to block this.
Kazuo Suzuki
Short hairpin RNAs
targeting the HIV-1
promotor region as a
strategy to sustain latency
Advances in tracking individual viral genomes to study reservoirs
Jake Estes:
Sensitive in situ detection of
SIV vRNA and vDNA
Useful to examine
-viral reservoirs
-anatomical location of latent genomes
Brandon Keele:
Ultra-deep barcoded SIVmac239 to
identify and quantify viral reservoirs
~10,000 unique
variants in stock
Infect at high
MOI (~1000
unique founder
viruses)
Useful tool to test various remission/cure
strategies in NHPs
Advances in vaccine research:
Eliciting neutralizing antibodies via “B-cell lineage vaccine design”
Natural infection:
dynamic co-evolution of virus and
host drives the emergence of
antibody neutralization breadth over
a period of months to years
B-cell lineage vaccine design:
recapitulate and accelerate antibody
evolution via sequential, iterative
vaccination with evolving envelope
antigens.
Dr. Anthony Fauci; Dr. Antonio Lanzavecchia
Penny Moore:
Challenge: Nab developmental pathways differ by epitope
V1V2 NAbs
Requires B-cell receptor
with a long CDR H3 –
these are very rare
CD4bs NAbs
-Highly mutated away from
common ancestor
-Maturation takes years
mature BnAb
UCA
mature BnAb
(high somatic
mutation)
YEARS
Liao et al Nature 2013
UCA with
long CDR H3
MONTHS
Doria-Rose et al Nature 2014
Engineered antibodies for treatment & prevention: ‘improving on nature’
Jia Guo:
Richard Koup:
A single-gene bi-specific
immunoadhesin
Non HIV-specific CD8 T cells in
germinal centers can be harnessed to
kill HIV-infected CD4+ T-cells using
bispecific antibodies containing antiCD3 and anti-gp120 domains
PGT128
PGT128
5A8
5A8
HIV-infected CD4 Tcell
SG-bispecific IA
-Encodes PGT128 (anti-glycan-V3) and
Hu5A (anti-CD4)
-neutralized 100% of viral isolates
tested.
KILL
VRC07-Fab
HIV env
CD8 T-cell
(not HIV-specific)
Anti-CD3 scFv
CD3
Jonah Sacha: RhCMV SIV 68-1 vaccine update:
protection by MHC-E Restricted CD8+ T cells
Science 2013
MHC-I
MHC-II
64% of the total RhCMV/gag-elicited CD8+
T cell responses were MHC-II-restricted!
RhCMV/SIV vector 68-1 induced CD8+ T cells are MHC-E restricted
MHC-I
MHC-E
MHC-II
not determined
-> MHC-E restricted CD8+ T cells recognize SIV infected cells
-> completely novel immune response against HIV
Advances in HIV virology: host restriction factors
MARCH8
Kenzo Tokunaga:
Novel restriction factor
MARCH8 blocks
envelope incorporation
into the virion, thereby
reducing viral infectivity
MX2
HERC5
Federica Gnudi:
MX2 rs2074560 G/G genotype
associated with reduced HIV-1
replication in vitro and protection
from HIV infection in vivo
Matthew Woods:
HERC5 interferes with REV/RREmediated nuclear export of HIV RNA
“The tissue is the issue”: moving immunology beyond the blood
Jake Estes:
After 20 weeks of suppressive cART in an SIV model:
-persistent low-level viral production in lymphoid tissues
-Incomplete reversal of GI damage
- sustained immune activation
Pre-cART
Post-cART
Genital and GI immunology: novel correlates of HIV acquisition
Laura Romas:
Godfrey Kigozi
HIV-exposed
seronegative female sex
workers express high
levels of IFNε in cervical
epithelium
HIV-exposed
seronegative MSM
overexpress
antiproteases in rectal
mucosa.
Presence of IL-8, MIG,
GM-CSF in foreskin
associated with increased
risk of HIV
seroconversion
IFNε
150
μm
AP 1
Shaheed Abdulhaqq
Control
HESN
Potential for novel microbicides or topical anti-inflammatories for prevention?
Genital and GI immunology: towards novel interventions
Alexandra Ortiz
Pb+IL21+ARV
p=0.03
ARV only
Days after infection
Blockade of the α4β7 integrin
delays vaginal SIV acquisition
% uninfected
% incidence-free
Treatment with probiotics and
IL21 reduced disease
progression and gut pathology in
ARV-treated macaques
Francois Villinger
α4β7
p=0.002
control
Weeks after SIV challenge
Reversing chronic immune activation in HIV: a role for HDACi?
Anne Sofie Kjær
Christian Apetrei
Phase I/II nonrandomized trial:
HDAC inhibitor romidepsin enhanced
virus replication and T-cell immune
activation in a novel SIV model system
Treatment with HDAC inhibitor
Panobinostat significantly reduces
markers of inflammation and
coagulation in chronic HIV infection
Highlights potential role for certain HDAC
inhibitors as anti-inflammatory agents
Summary and conclusions
AIDS 2014 Track A featured exciting advances in HIV cure
and vaccine research, as well as basic and translational
research in the immunovirology of HIV/SIV infection
The city of Vancouver looks forward to
welcoming you to IAS 2015