www.ias2011.org

Barbara Ensoli, MD, PhDNational AIDS Center

Istituto Superiore di SanitàRome, 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)

www.ias2011.org

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 (VL50 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

www.ias2011.org

0

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7.5 μg (3x) 7.5 μg (5x) 30 μg (3x) 30 μg (5x)

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dy

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) IgM IgG IgA Total

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IFN IL-2 IL-4

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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

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B c

ells

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t-test for paired data: *p<0.05

ISS T-002 and OBS studies - CD4+ T cells and B cellsChanges from baseline

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-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.00.20.40.60.81.01.21.41.61.82.02.22.4

w12 w20 w48 w72 w96 w12 w20 w48 w72 w96

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-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.00.20.40.60.81.01.21.41.61.82.02.22.4

w12 w20 w48 w72 w96

ISS T-002 and OBS studies - T regulatory Cells

Changes from baseline

** *

**

**

T-002 OBS

T-reg increase was associated with reduction of immune activation and inflammation markers (CD38+/CD8+ T cells, neopterin, 2-microglobulin, total IgG)

t-test for paired data: *p<0.05

www.ias2011.org

25.7 28.1 27.1 27.8 30.6 29.3 33.2

53.1 50.4 50.7 49.4 49.1 48.5 44.9

21.1 21.5 22.1 22.8 20.3 22.3 21.9

0%

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w0 w8 w12 w20 w48 w72 w84

CD

8 T

cel

ls (

%)

CD8 naive CD8 Tem CD8 Tcm

29.5 26.4 25.1 28.7 30.0 29.5 36.3

24.322.8 24.5 22.8 24.8 19.6

16.2

46.2 50.7 50.4 48.5 45.3 50.8 47.5

0%

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w0 w8 w12 w20 w48 w72 w84

CD

4 T

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ls (

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CD4 naive CD4 Tem CD4 Tcm

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

* *

* * *

* * *

t-test for paired data: *p<0.05

www.ias2011.org

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IL-2 IL-4

Anti-Candida Anti-CEFAnti-Env

IL-2 IL-4 IL-2 IL-4

CD4 CD8 CD4 CD8 CD4 CD8

**

*

**

**

*

IFN- IFN- IFN-

**

****

**

***

**

ISS T-002 Cellular Immune Response

Baseline

Up to Week 48

*

McNemar’s Test: *p<0.05; **p<0.01

www.ias2011.org

ISS T-002 Conclusions

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

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)

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 of CD4+ T

cells and B lymphocytes, increases of naïve and central memory CD4+ and CD8+ T

cell subsets, reduction of effector memory CD4+ and CD8+ T cells, and with

increases of T cell responses against Env and recall antigens (Candida, CMV, EBV,

Flu)

More immune-compromised individuals experienced greater therapeutic effects

www.ias2011.org

ACKNOWLEDGMENTS

JOINT ISS/S. GALLICANOCORE LABORATORY SITEA. TripicianoV. FrancavillaA. ScoglioM. CampagnaM. Ruiz-AlvarezD. ScaramuzziF. StivaliA. ArancioG. PanicciaC. AriolaF. Ensoli

NATIONAL AIDS CENTER – ISS

CLINICAL TRIALS DIVISIONO. LongoS. BellinoC. SgadariS. MarcotullioF. CammisaG. Fornari Luswergh

AVITECH-DIATHEVA SRLE. LaguardiaM. Magnani

INJECTALIA SRL

C R O-OPERA SRL

S. De NaroE. OttonelloL. MichelliniG. BergamaschiF. MontanaroO. PicconiN. Ngo DinhF. Barattini

VIRUS-HOST INTERACTION ANDCORE LAB OF IMMUNOLOGYDIVISIONA. CafaroS. MorettiM.R. Pavone CossutG. BarillariP. Monini

AIDS Help-Line, ISSA. LuziA. ColucciP. GalloR. ValliA. SantoroA. D’Agostini

CLINICAL SITESOspedale A. di Savoia, TorinoOspedale S. Raffaele, MilanoOspedale Sacco, MilanoSpedali Civili, BresciaAzienda Osp. San Gerardo, MonzaArcispedale S. Anna, FerraraPoliclinico Universitario, ModenaOspedale S. M. Annunziata, FirenzeIFO - San Gallicano, RomaOspedale S.M. Goretti, LatinaPoliclinico Universitario, Bari

CABGay Center: A. PotoNADIR Onlus: R. BiondiGITA:V. CantarellaNPS: M. Formisano

DSMBP. Popoli - ItalyM.J. Mirò - SpainV. Miller - USAF. Menniti Ippolito - Italy

IABJ. Holmgren - SwedenJ.A. Levy - USAF. Goebel - GermanyC.A. Guzman - GermanyL. Moretta - ItalyS. Osmanov - SwitzerlandG.V. Zuccotti - ItalyA. Cassone - ItalyK. Moelling - Switzerland