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Track A – Basic Science
Final Report
Giulia Marchetti
Dept of Medicine, Surgery and Dentistry – Clinic of Infectious Diseases –
University of Milan, San Paolo Hospital, Milan, Italy
www.ias2011.org
PREVENTION
In the era of PrEP and treatment as
prevention, do we still need vaccine?
Vaccine is given once
Durable protection
Cost-effectiveness
G Nable, IAS 2011
www.ias2011.org
Vaccine research
• Gary Nable (USA)- The changing face of HIV vaccine
research
– development of resurfaced stabilized cores that can be used as
probes for Human neutralizing antibodies and templates for
immunogens
– VRC01 Ab: neutralise 90% natural circulating viruses; determined
the crystal structure of VRC01 in complex with a HIV-1 gp120 core;
VRC01 partially mimics CD4 interaction with gp120
– A shift from the CD4-defined orientation, however, focuses VRC01
onto the vulnerable site of initial CD4 attachment, allowing it to
overcome the glycan and conformational masking that diminishes
the neutralization potency of most CD4-binding-site antibodies
– maturation of VRC01 can now be reconstituted in laboratory
settings- immunogen (vaccine research); passive transfer
www.ias2011.org
Vaccine research
•
Barbara Ensoli (Italy)
– vaccine involving a combination of HIV Tat and Env: efficacious in protecting
macaques from mucosal SHIV challenge.
•
•
•
•
Susan Zolla-Pazner (USA) “Structural Vaccinology Approach”
– cross-clade neutralizing antibodies using a gp120 DNA-based prime
followed by a boost with a Env V3 attached to a Cholera Toxin B protein
scaffold immunogen.
Susan Barnet (USA)
– results from the RV144 trial and other studies utilizing non-human
primates, which suggest that vaccine protection from HIV is an achievable
goal.
– identify a candidate that will provide this type of protection in humans.
David Weiner (USA)
– “enhanced” DNA vaccine candidate: DNA containing consensus
sequences of the target antigen combined with better delivery methods,
such as tissue electroporation, and an IL-12 adjuvant - robust cell immune
responses.
Felipe Garcia (USA)
– dendritic cell based vaccine strategies.
– HIV-specific responses and reduction in viral load in a limited number of
individuals.
www.ias2011.org
Time to consider a combination
approach to biomedical interventions
Robin Shattock (UK)
• Mucosal exposure in the context of PrEP influence immune response
(animal models)
• VAXPrEP could deliver better protection by providing protection during
immunization period, reducing infectious challenge, and increasing
eclipse phase providing an extended opportunity for adaptive immunity
to respond.
• Vaccine candidates can be co-formulated with microbicides
– Gp120 stable within genital gels
– mucosal vaccination boost localized immunity
www.ias2011.org
RESERVOIRS AND STRATEGIES
TO ELIMINATE RESERVOIRS
•CCR6: marker for memory T-cells imprinted with a transcriptional
program favorable to HIV replication – LB Gosselin Canada
•Lymph nodes reservoirs and alteration/dysregulation- LB J. Zaunders
Australia; J Mudd USA
•TH22 cells: gut HIV reservoir and immune activation on HAART – KIM
(Canada)
www.ias2011.org
GAMMA-CHAIN CYTOKINES – HAART
INTENSIFICATION
IL-7 & IL-15 - IL-7 resulted in higher proportion of proliferating
Ki67+CD4+, but viral reactivation was increased only following IL-15
stimulation. Strategy to deplete the latent HIV reservoir - C.
Vandergeeten
RALTEGRAVIR INTENSIFICATION –
•
In virologically suppressed patients on stable long-term HAART,
intensification with raltegravir did not result in decay of HIV viral
reservoirs in GALT CD4+ T-lymphocytes obtained from sigmoid colon
biopsies at 48 weeks of follow up - J. Brunetta
• RAL intensification significantly accelerated the decay of latently
infected CD4+ memory T cells, with no evidence of an effect on viral
replication. - C. Gutiérrez
www.ias2011.org
MECHANISMS OF DISEASE
PROGRESSION
•Naïve T cell recruitment is not the major source of CD4+ memory
T cell production after infection; CD4+ memory T cells are
intrinsically capable of self-renewal– LB A. OKOYE USA
www.ias2011.org
• Intestinal microbioma as driver of inflammation?
– Greater representation of proinflammatory/inflammationthriving class-level bacteria. Unique distributions of bacteria
in samples from different anatomical sites which were not
clearly impacted by HAART therapy – CL Ellis
• Tryptophan catabolism as correlate of HIV disease progression
and mortality?
– Lower pretreatment tryptophan predict slower CD4+
recovery after 12 months therapy; lower pretreatment/month
6 tryptophan predict death, also adjusting for self-reported
dietary protein intake – P Hunt
IMMUNE
ACTIVATION/INFLAMMATION AND
HIV DISEASE
or
WHAT DO WE KNOW (AND WHAT
WE DO NOT KNOW) ON HOW HIV
CAUSES AIDS?
www.ias2011.org
• The facts:
– Immune activation predicts disease progression and
response to HAART;
– Immune activation persists on virologically-suppressive
HAART;
– Immune activation/inflammation on HAART associates
to non-infectious complications
The questions:
o What drives immune activation on HAART?
o How can we target immune activation as an anti-HIV
therapy?
www.ias2011.org
• Possible mechanisms behind elevated activation upon
virologically-suppressive HAART– S. Deeks (USA)
– Frequencies of PD-1+-expressing CD4+ T cells and cell-based measures of
viral persistence were elevated in treated patients with low CD4+ T cell
counts, suggesting that these individuals may be more difficult to cure and
will require unique interventions- LB- Hatano, USA
• Biomarkers of inflammation/coagulation: associations (and
predictive role of) with
– end-organ disease - J. Lundgren (Denmark);
– metabolic complications - G. Behrens (Germany)
• Hepatic flares in HIV/HCV and/ore HBV-co-infected patients after ART
initiation are associated with high anti-inflammatory cytokine and HA
(hyaluronic acid) levels; biomarkers indicative of inflammation and
coagulation are associated with death – LB- I Sereti (USA)
HOW DO WE MOVE FORWARD?
– MODELS OF PROTECTION
• Non-pathogenicity of SIV-1 for African monkeys (get infected, present viremia,
present immune activation only during acute infection) - M Mueller-Trutwin
(France)
• Elite controllers
– VIRAL DETERMINANTS OF AIDS PATHOGENESIS
• Which of the features that HIV genes acquired are critical for the immune activation
and the infection outcome - F Kirchhoff (Germany)
– INTERVENTIONAL TRIALS
• “Interventional Trials targeting key pathways of “activation” can concurrently test
hypotheses of pathogenesis and also explore promising treatment strategies for
persons at risk for morbidity” – M Lederman (USA) – PANEL CONSENSUS
– APPROACHES TO BLOCK INFLAMMATION/IMMUNE ACTIVATION– A
Landay, P. Hunt (USA)
www.ias2011.org
– MODELS OF PROTECTION
• Non-pathogenicity of SIV-1 for African monkeys (get infected, present
viremia, present immune activation only during acute infection) - M
Mueller-Trutwin (France)
• Elite controllers
– VIRAL DETERMINANTS OF AIDS PATHOGENESIS
• Which of the features that HIV genes acquired are critical for the immune
activation and the infection outcome - F Kirchhoff (Germany)
– INTERVENTIONAL TRIALS
• “Interventional Trials targeting key pathways of “activation” can
concurrently test hypotheses of pathogenesis and also explore promising
treatment strategies for persons at risk for morbidity” – M Lederman
(USA) – PANEL CONSENSUS
– APPROACHES TO BLOCK INFLAMMATION/IMMUNE ACTIVATION– A
Landay, P. Hunt (USA)
www.ias2011.org
MODELS OF PROTECTION- the
monkey model
•
Experimental depletion of CD25+CD4+ Treg (i.e. induction of immune
activation ) in SIV-infected agm: delayed control of viral replication and
of CD4+ T cell recovery despite no AIDS - I. Pandrea (USA)
• Reduced CCR5 expression on SM CD4+ TCM partially protects these
cells from SIV infection, thus favoring CD4+ T-cell homeostasis – B
Cervasi (USA)
– Alternative receptor usage in SM? – N.E. Riddick (USA)
– Maintenance of IL-21 producing CD4+ T-cells in SM? – M. Paiardini
(USA)
• The ability of stimulated DN cells to produce Th1 and Th2 cytokines at
levels comparable to CD4 cells indicates their potential to compensate
for low CD4 levels in CD4-low SIV-infected SMs – D Sodora (USA)
www.ias2011.org
MODELS OF PROTECTION- the
“human model”
• Why do elite controllers have high T-cell activation but low HIV
RNA?
• TNFα-skewed Gag and Nef specific CD8+ T cell profile and Microbial
translocation in EC - M. Lopez (SPAIN); also S. DESAI (USA); ON
THYMUS: XU YU (USA), ON FUNCTION: L.A. CHAKRABARTI
(FRANCE)
• p21 acts as an intrinsic inhibitor of CDK9-mediated transcriptional
elongation of HIV-1 in CD4 T cells from elite controllers- M.
Lichterfeld (USA)
• REDUCED MACROPHAGE INFECTION: A. SAEZ-CIRION
(FRANCE)
www.ias2011.org
– MODELS OF PROTECTION
• Non-pathogenicity of SIV-1 for African monkeys (get infected, present viremia,
present immune activation only during acute infection) - M Mueller-Trutwin
(France)
• Elite controllers
– VIRAL DETERMINANTS OF AIDS PATHOGENESIS
• Which of the features that HIV genes acquired are critical for the immune
activation and the infection outcome - F Kirchhoff (Germany)
– INTERVENTIONAL TRIALS
• “Interventional Trials targeting key pathways of “activation” can concurrently test
hypotheses of pathogenesis and also explore promising treatment strategies for
persons at risk for morbidity” – M Lederman (USA) – PANEL CONSENSUS
– APPROACHES TO BLOCK INFLAMMATION/IMMUNE ACTIVATION– A Landay, P.
Hunt (USA)
www.ias2011.org
• High degree of HIV-1 group M genetic variability in North Angolan
population, challenging diagnostic, treatment and prevention of HIV-1
in this low HIV/AIDS prevalence country - J.F. MACHADO DE
MORAIS AFONSO (Brasil, Angola)
• Attenuation of in vitro viral replication capacity in HIV-1 clade B
subtype viruses circulating in Japan between 1993-2009 – S
NOMURA (TOKYO)
• Nef can inactivate ABCA1 by blocking the interaction between this
cholesterol transporter and calnexin, the cellular endoplasmic
reticulum chaperone involved in regulation of folding and maturation of
glycosylated proteins - M. BUKRINSKY (USA)
www.ias2011.org
MODELS OF PROTECTION
• Non-pathogenicity of SIV-1 for African monkeys (get infected, present
viremia, present immune activation only during acute infection) - M
Mueller-Trutwin (France)
• Elite controllers
– VIRAL DETERMINANTS OF AIDS PATHOGENESIS
• Which of the features that HIV genes acquired are critical for the immune
activation and the infection outcome - F Kirchhoff (Germany)
– INTERVENTIONAL TRIALS
• “Interventional Trials targeting key pathways of “activation” can
concurrently test hypotheses of pathogenesis and also explore promising
treatment strategies for persons at risk for morbidity” – M Lederman
(USA) – PANEL CONSENSUS
– APPROACHES TO BLOCK INFLAMMATION/IMMUNE ACTIVATION– A
Landay, P. Hunt (USA)
www.ias2011.org
• Chloroquine : Activation inhibitor
• Statins/anti-IL-6: Inflammation inhibitors
• Rifaxamin/Sevalamer: MT inhibitors
• Multinational 4-week Phase IIa, double blinded, placebo
controlled study OF AntiViral-HyperActivation Limiting
Therapeutics (AV-HALT VS411), a novel fixed-dose
combination of an antiviral and an antiproliferative drug:
– Within 28 days treatment AV-HALTs decrease the
degree of naïve cells proliferation allowing the
replenishment of the naïve cells pool- LB - F. Lori
(Italy)
www.ias2011.org
ANTIVIRAL IMMUNITY AND
TRANSMISSION
www.ias2011.org
• Human stem cell-based gene therapy to engineer
HIV-specific T-cell immunity can elicit functional
anti-viral CTL in vivo S. KITCHEN (USA)
• Non-human primate model of penile transmission
(RM- SIVMAC251): SIV can be transmitted by
penile SIV exposure but is ~50% less efficient
than vaginal challenge B. KEELE (USA)
• Genetic variations in Defensins and TLRs may
affect host-virus interactions and impact the
disease progression K. GIANESIN, ITALY
www.ias2011.org
HIV CO-INFECTIONS: THE AXIS
OF THE EVIL
www.ias2011.org
•
CRYPTOCOCCAL MENINGITIS:
– Enhanced immunoregulatory/activated phenotype of CNS NK
(chemoattraction via CXCL-10/CXCR3) - V. NARANBHAI
(Durban- South Africa)
– Enriched CD4/CD8 TEM CCR5 AND CXCR3-expressing in CSF ,
and CD4+ TEM in CSF in C-IRIS VS. NON-C-IRIS - C.C. CHANG
M.A. FRENCH (Australia)
• Placenta malaria associated with increased risk of MTCT of HIV-1
(aOR = 6.5; 1.4-30.9), especially among primigravidae (aOR = 12.0;
1.0-150; p< 0.05) - P. BULTERYS (USA/Rwanda)
• GBV-C infection reduces B/NK activation and monocyte CCR5 surface
expression -J.T. STAPLETON (USA)
• Destruction of nervous cells is potentiated in the simultaneous
presence of gp41 and Toxoplasma gondii- E.E. ESCOBAR GUEVARA
(Venezuela)
www.ias2011.org
DRUG DEVELOPMENT AND
RESISTANCE
www.ias2011.org
• 1% Tenofovir gel (CAPRISA 004), has a direct antiherpetic activity:
– (i) it inhibits HSV-1 and HSV-2;
– (ii) reduces HSV-1 and HSV-2 replication at different
sites;
• Topical drug administration appears to be a key
requirement to enable this dual prophylactic effect of
tenofovir - L. MARGOLIS (USA)
www.ias2011.org
Leonid Margolis &
Cristophe Vanpouille, USA
Scott G Kitchen, USA
A Special Thanks To:
Camilla Tincati,
Andrea Nannipieri
Valentina
Svicher,
Roma
Alessandra La
Palombara
and all the volunteers at
the Rapporteur Office
www.ias2011.org
THE ITALIAN GOVERNMENT STILL OWES 260
MILLION EUROS TO THE GLOBAL FUND AND
NEVER PLEDGED FOR 2011 - 2013
ITALY:
KEEP THE PROMISE, NOW!
FUND THE FUND, NOW!
AIDS, TUBERCOLOSIS AND
MALARIA WILL NOT WAIT!
www.ias2011.org