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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

• 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?

• 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!