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![Page 1: Www.ias2011.org Track A – Basic Science Final Report Giulia Marchetti Dept of Medicine, Surgery and Dentistry – Clinic of Infectious Diseases – University.](https://reader035.fdocuments.net/reader035/viewer/2022062717/56649e1a5503460f94b083f8/html5/thumbnails/1.jpg)
www.ias2011.org
Track A – Basic ScienceFinal Report
Giulia Marchetti
Dept of Medicine, Surgery and Dentistry – Clinic of Infectious Diseases – University of Milan, San Paolo Hospital, Milan, Italy
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PREVENTION
In the era of PrEP and treatment as prevention, do we still need vaccine?
Vaccine is given onceDurable protectionCost-effectiveness
G Nable, IAS 2011
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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
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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.
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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
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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)
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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
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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
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• Intestinal microbioma as driver of inflammation?
– Greater representation of proinflammatory/inflammation-thriving 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
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IMMUNE ACTIVATION/INFLAMMATION AND
HIV DISEASEor
WHAT DO WE KNOW (AND WHAT WE DO NOT KNOW) ON HOW HIV
CAUSES AIDS?
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• 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?
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• 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)
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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)
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– 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)
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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)
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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)
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– 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)
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• 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)
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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)
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• 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)
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ANTIVIRAL IMMUNITY AND
TRANSMISSION
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• 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
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HIV CO-INFECTIONS: THE AXIS OF THE EVIL
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• 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)
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DRUG DEVELOPMENT AND RESISTANCE
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• 1% Tenofovir gel (CAPRISA 004), has a direct anti-herpetic 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)
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Leonid Margolis & Cristophe Vanpouille, USA
Scott G Kitchen, USA
Valentina Svicher, Roma
A Special Thanks To:
Camilla Tincati, Andrea Nannipieri
Alessandra La Palombara
and all the volunteers at the Rapporteur Office
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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!