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Barbara Ensoli, MD, PhD National AIDS Center Istituto Superiore di Sanità Rome, Italy

Barbara Ensoli, MD, PhD National AIDS Center Istituto Superiore di Sanità Rome, Italy. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART (phase II trial, ISS T-002).

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Barbara Ensoli, MD, PhD National AIDS Center Istituto Superiore di Sanità Rome, Italy

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  1. Barbara Ensoli, MD, PhD National AIDS Center Istituto Superiore di Sanità Rome, Italy Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART (phase II trial, ISS T-002)

  2. Effective HAART is often unable to restore immune homeostasis and is associated with novel non-AIDS-defining diseases • CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals still express multi-spliced transcripts encoding HIV regulatory proteins (e.g. Tat, Nef) • A phase II randomized, open label, multicentric clinical trial with Tat given 3 or 5 times monthly at 7.5 or 30 g doses (ISS T-002, Clinicaltrials.gov: NCT00751595) was conducted in 160 individuals under effective HAART (VL50 copies/ml) with CD4+ T cell counts 200 cells/L and any pre-HAART CD4 nadir • Eighty-eight individuals enrolled with the same criteria in a parallel prospective observational study at the same clinical sites (ISS OBS T-002, Clinicaltrials.gov: NCT01024556) were examined as reference group

  3. IFN IL-2 IL-4 * ** * CD4 T cell proliferation CD8 T cell proliferation * * ** ISS T-002 Humoral and cellular immune response against Tat Anti-Tat Ab response: p=0.0139 (Chi-Square for Trend) McNemar’s Test: *p<0.05; **p<0.01

  4. ISS T-002 and OBS studies - CD4+ T cells and B cells Changes from baseline T-002 OBS * * * t-test for paired data: *p<0.05

  5. ISS T-002 and OBS studies - T regulatory Cells Changes from baseline T-002 OBS * * * * * * * t-test for paired data: *p<0.05 T-reg increase was associated with reduction of immune activation and inflammation markers (CD38+/CD8+ T cells, neopterin, 2-microglobulin, total IgG)

  6. ISS T-002 CD4+ and CD8+ T cells phenotype * * * * * * * * t-test for paired data: *p<0.05

  7. Baseline Up to Week 48 ISS T-002 Cellular Immune Response Anti-Env Anti-Candida Anti-CEF IFN- IL-2 IL-4 IFN- IL-2 IL-4 IFN- IL-2 IL-4 ** ** ** ** * * CD4 CD4 CD8 CD4 CD8 CD8 ** ** * * * * ** ** McNemar’s Test: *p<0.05; **p<0.01

  8. ISS T-002 Conclusions • Immunization with Tat was safe and induced durable humoral and cellular anti-Tat immune responses • Increase of T-reg and reduction of immune activation (CD38 expression on CD8+ T cells and biochemical markers)were associated with stable increases ofCD4+ T cells and B lymphocytes, increases of naïve and central memory CD4+ and CD8+ T cell subsets, reduction ofeffector memory CD4+ and CD8+ T cells, andwith increases of T cell responses against Env and recall antigens (Candida, CMV, EBV, Flu) • More immune-compromised individuals experienced greater therapeutic effects These findings indicate that Tat immunization represents a promising therapeutic tool to intensify HAART efficacy and to restore the immune homeostasis (B. Ensoli et al., PLoS ONE, 2010) A phase II randomized, double blinded, placebo controlled, therapeutic trial of Tat immunization in 200 ARV-treated, virologically suppressed individuals with CD4+ T cells 200/μL is starting in South Africa (ISS T-003) in cooperation with NDOH and SAAVI

  9. ACKNOWLEDGMENTS NATIONAL AIDS CENTER – ISS CLINICAL SITES Ospedale A. di Savoia, Torino Ospedale S. Raffaele, Milano Ospedale Sacco, Milano Spedali Civili, Brescia Azienda Osp. San Gerardo, Monza Arcispedale S. Anna, Ferrara Policlinico Universitario, Modena Ospedale S. M. Annunziata, Firenze IFO - San Gallicano, Roma Ospedale S.M. Goretti, Latina Policlinico Universitario, Bari C R O-OPERA SRL CLINICAL TRIALS DIVISION O. Longo S. Bellino C. Sgadari S. Marcotullio F. Cammisa G. Fornari Luswergh S. De Naro E. Ottonello L. Michellini G. Bergamaschi F. Montanaro O. Picconi N. Ngo Dinh F. Barattini JOINT ISS/S. GALLICANO CORE LABORATORY SITE • Tripiciano • V. Francavilla • A. Scoglio • M. Campagna • M. Ruiz-Alvarez • D. Scaramuzzi • F. Stivali • A. Arancio • G. Paniccia • C. Ariola • F. Ensoli AVITECH-DIATHEVA SRL E. Laguardia M. Magnani DSMB P. Popoli - Italy M.J. Mirò - Spain V. Miller - USA F. Menniti Ippolito - Italy INJECTALIA SRL AIDS Help-Line, ISS A. Luzi A. Colucci P. Gallo R. Valli A. Santoro A. D’Agostini IAB J. Holmgren - Sweden J.A. Levy - USA F. Goebel - Germany C.A. Guzman - Germany L. Moretta - Italy S. Osmanov - Switzerland G.V. Zuccotti - Italy A. Cassone - Italy K. Moelling - Switzerland VIRUS-HOST INTERACTION AND CORE LAB OF IMMUNOLOGY DIVISION A. Cafaro S. Moretti M.R. Pavone Cossut G. Barillari P. Monini CAB Gay Center: A. Poto NADIR Onlus: R. Biondi GITA:V. Cantarella NPS: M. Formisano

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