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Track A Basic Science Final Report

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. Vaccine research. Gary Nable (USA)- The changing face of HIV vaccine researchdevelopment of resurfaced stabilized cores that can

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Track A Basic Science Final Report

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    1. 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

    2. PREVENTION

    3. 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 High diversity of HIV envelope . Dr. Nabel reported on the development of resurfaced stabilized cores that can be used as probes for Human neutralizing antibodies and templates for immunogens. He identified VRC01 that not only neutralizes 90% of natural circulating viruses but also confers sterile protection against mucosal challenge in non-Human primates. Independent VRC01-like antibodies have been isolated from multiple individuals. Furthermore, the maturation of VRC01 can now be reconstituted in laboratory settings, opening a new window of research on HIV neutralizing antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors High diversity of HIV envelope . Dr. Nabel reported on the development of resurfaced stabilized cores that can be used as probes for Human neutralizing antibodies and templates for immunogens. He identified VRC01 that not only neutralizes 90% of natural circulating viruses but also confers sterile protection against mucosal challenge in non-Human primates. Independent VRC01-like antibodies have been isolated from multiple individuals. Furthermore, the maturation of VRC01 can now be reconstituted in laboratory settings, opening a new window of research on HIV neutralizing antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors

    4. 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. High diversity of HIV envelope . Dr. Nabel reported on the development of resurfaced stabilized cores that can be used as probes for Human neutralizing antibodies and templates for immunogens. He identified VRC01 that not only neutralizes 90% of natural circulating viruses but also confers sterile protection against mucosal challenge in non-Human primates. Independent VRC01-like antibodies have been isolated from multiple individuals. Furthermore, the maturation of VRC01 can now be reconstituted in laboratory settings, opening a new window of research on HIV neutralizing antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors High diversity of HIV envelope . Dr. Nabel reported on the development of resurfaced stabilized cores that can be used as probes for Human neutralizing antibodies and templates for immunogens. He identified VRC01 that not only neutralizes 90% of natural circulating viruses but also confers sterile protection against mucosal challenge in non-Human primates. Independent VRC01-like antibodies have been isolated from multiple individuals. Furthermore, the maturation of VRC01 can now be reconstituted in laboratory settings, opening a new window of research on HIV neutralizing antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors

    5. 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 Imperial College London HIV annual incidence has declined, but number of pts living with HIV continues to rise and HIV prevalence is constant at 0.8% of global population since 2011, Only 30% of people have access Need of combination prevention (behavioural changes, HAART, social justice/human rights, biomedical strategies)Imperial College London HIV annual incidence has declined, but number of pts living with HIV continues to rise and HIV prevalence is constant at 0.8% of global population since 2011, Only 30% of people have access Need of combination prevention (behavioural changes, HAART, social justice/human rights, biomedical strategies)

    6. RESERVOIRS AND STRATEGIES TO ELIMINATE RESERVOIRS SIV infects follicuINFECTS FOLLICULAR HELPER T CELLS IN LYMPH NODES DURING PATHOGENIC INFECTION OF PIGTAIL MACAQUESIV infects follicuINFECTS FOLLICULAR HELPER T CELLS IN LYMPH NODES DURING PATHOGENIC INFECTION OF PIGTAIL MACAQUE

    7. 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 Nunnari: DIFFERENT DATA SHOWING PURIFICTION OF RESTING MEMORY CD4 IL7 E’ IL + FORTE STIMOLATORE DI VIRAL PRODUCTION Reservoirs formed during acute hiv. Mainly memory cd4, mechanims is homeosttic prolifertaion , il7 e 15 involved in maintentnce memory. Il-7 5214 actg given il-7: aumento ki67cd4, no inreased hiv dna in cd4 ma quando normlizzano per nume cd4 sě.. Poi cd4 stimulati con il7=genetic diversity Cd4 stim con 7 e 15: viability (=il7 e15); proliferation ki67 dr, pd1, 7 aumenta ki67 >>il15, =altri marker. Cd4 stim con citoch e art, non viral rna in il7 sě in il15 (RT-pcr in SN). PRENDI SLIDE FINALE.Nunnari: DIFFERENT DATA SHOWING PURIFICTION OF RESTING MEMORY CD4 IL7 E’ IL + FORTE STIMOLATORE DI VIRAL PRODUCTION Reservoirs formed during acute hiv. Mainly memory cd4, mechanims is homeosttic prolifertaion , il7 e 15 involved in maintentnce memory. Il-7 5214 actg given il-7: aumento ki67cd4, no inreased hiv dna in cd4 ma quando normlizzano per nume cd4 sě.. Poi cd4 stimulati con il7=genetic diversity Cd4 stim con 7 e 15: viability (=il7 e15); proliferation ki67 dr, pd1, 7 aumenta ki67 >>il15, =altri marker. Cd4 stim con citoch e art, non viral rna in il7 sě in il15 (RT-pcr in SN). PRENDI SLIDE FINALE.

    8. MECHANISMS OF DISEASE PROGRESSION

    9. 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

    10. IMMUNE ACTIVATION/INFLAMMATION AND HIV DISEASE or WHAT DO WE KNOW (AND WHAT WE DO NOT KNOW) ON HOW HIV CAUSES AIDS?

    11. 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

    12. 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)

    13. 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) Mettere LB (check which) and part of session TUPD01 (check which)Mettere LB (check which) and part of session TUPD01 (check which)

    14. 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) Mettere LB (check which) and part of session TUPD01 (check which)Mettere LB (check which) and part of session TUPD01 (check which)

    15. 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)

    16. MODELS OF PROTECTION- the “human model” Why do elite controllers have high T-cell activation but low HIV RNA? TNFa-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)

    17. 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) Mettere LB (check which) and part of session TUPD01 (check which)Mettere LB (check which) and part of session TUPD01 (check which)

    18. 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) 96 pts. THEY ARE NOW PERFORMING FURTHER STUDIES TO UNDERSTAND RC OR IMMUNE RESPONSE (FITNESS) TO SEE IF THESE MODIFICATIONS HAVE BIOLOGICAL RELAPSES These results can provide the molecular basis underlying the onset of atherosclerosis of HIV-1 infected patients. 96 pts. THEY ARE NOW PERFORMING FURTHER STUDIES TO UNDERSTAND RC OR IMMUNE RESPONSE (FITNESS) TO SEE IF THESE MODIFICATIONS HAVE BIOLOGICAL RELAPSES These results can provide the molecular basis underlying the onset of atherosclerosis of HIV-1 infected patients.

    19. 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) Mettere LB (check which) and part of session TUPD01 (check which)Mettere LB (check which) and part of session TUPD01 (check which)

    20. 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 naďve cells proliferation allowing the replenishment of the naďve cells pool- LB - F. Lori (Italy) WELBX03 - Depletion of naďve CD4+T cell compartment by immune hyperactivation can be rapidly reversed by AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs) D.V. Baev1, F. Lori1 Multinational 4-week Phase IIa, double blinded, placebo controlled study OF AV-HALT VS411, a novel fixed-dose combination of an antiviral (low-dose, slow-release 2 ´,3 ´-dideoxyinosine) and an antiproliferative drug (low-dose hydroxycarbamide) (32 PTS). Within 28 days treatment AV-HALTs decrease the degree of naďve cells proliferation allowing the replenishment of the naďve cells pool. WELBX03 - Depletion of naďve CD4+T cell compartment by immune hyperactivation can be rapidly reversed by AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs) D.V. Baev1, F. Lori1

    21. ANTIVIRAL IMMUNITY AND TRANSMISSION

    22. 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

    23. HIV CO-INFECTIONS: THE AXIS OF THE EVIL

    24. 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)

    25. DRUG DEVELOPMENT AND RESISTANCE

    26. 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) Ln vagina, cervix + hiv /hsv- orally conc lower , acts on hs dna polimerae . Tutto il punto č sulla concentrazione che si raggiunge topically. 1% tenofovir vaginal gel reduced the risk of HIV-1 acquisition by 39% (South African women), and a 51% decrease in the risk of HSV2 infection. The active metabolite tenofovir diphosphate is generated in human cell cultures, and effectively inhibits HSV DNA polymerase Ln vagina, cervix + hiv /hsv- orally conc lower , acts on hs dna polimerae . Tutto il punto č sulla concentrazione che si raggiunge topically. 1% tenofovir vaginal gel reduced the risk of HIV-1 acquisition by 39% (South African women), and a 51% decrease in the risk of HSV2 infection. The active metabolite tenofovir diphosphate is generated in human cell cultures, and effectively inhibits HSV DNA polymerase

    27. Thanks What I would like to achieve in the next 20 minutes is to take you for a walk through the intricacies of HIV/AIDS pathogenesis, particularly with respect to the interaction between the virus and the host immune system, and discuss some implications of these “intricacies” in terms of AIDS therapy and vaccines.Thanks What I would like to achieve in the next 20 minutes is to take you for a walk through the intricacies of HIV/AIDS pathogenesis, particularly with respect to the interaction between the virus and the host immune system, and discuss some implications of these “intricacies” in terms of AIDS therapy and vaccines.

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