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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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slide1
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)

slide2

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
slide3

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

slide4

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

slide5

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)

slide6

ISS T-002 CD4+ and CD8+ T cells phenotype

*

*

*

*

*

*

*

*

t-test for paired data: *p<0.05

slide7

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

slide8

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

slide9

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