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TBIRIS
HIV/AIDS
Framework programme: 6
Call: 4
Project number: LSHP-CT-2007-037659
EC contribution: € 2,475,482
Duration: 36 Months
Type: STREP
Starting date: January 2007
Graphic element Pathogenesis and identification of predictive factors of TB-IRIS in HIV patients under HAART
Keywords: Undesirable effect, ART, IRIS, developing countries, Tuberculosis, HIV,

Summary:

The Immune Reconstitution Inflammatory Syndrome (IRIS) is an undesirable effect of effective antiretroviral therapy (ART) in HIV-infected patients. It is a pathological inflammatory response against microorganisms, which are "recognized" as new by the regenerating immune system in response to ART. Tuberculosis-associated IRIS (TB-IRIS) is expected to become a major cause of HIV-associated morbidity as an increasing number of patients have access to ART in areas where both HIV infection and TB are endemic.

The lack of a clear-cut case-definition and reliable predictive markers make clinical management of TB-IRIS less efficient. The exact immunopathological mechanisms underlying TB-IRIS are not known. It is hereby put forward that TBIRIS occurs when immunity is unevenly reconstituted after ART and in the presence of a high burden of M tuberculosis antigens.

The overall aim of this study is to understand the pathogenesis of TB-IRIS, and to define its determinants by conducting a comprehensive investigation of clinical, virological, immunological and molecular parameters in a cohort of HIV-infected patients with different levels of exposure to TB. The occurrence of TB-IRIS will be used as the outcome variable. The clinical presentation of TBIRIS will be assessed and the predictive value of different biological markers of HIV infection and tuberculosis (including the immune response induced by the novel TB protein HBHA), will be evaluated. Parallel to the clinical studies, there will be a study on whether defective reconstitution patterns associated with TB-IRIS can be linked to 3 types of key player cells. Cellular and molecular immunology techniques to characterize aberrant restoration profiles of regulatory T cells, effector T cells and monocyte/macrophages that are associated with TB-IRIS will be used. Results will be used to formulate guidelines for the diagnosis and therapy of TB-IRIS and to define clinically relevant predictors for the occurrence of TBIRIS.

Background:

IRIS is considered to be a clinical deterioration after the introduction of ART, due to an exaggerated inflammatory reaction against an antigen (viable or not), associated with a (partial) reconstitution of the immune responses against this antigen. IRIS has been described to occur in up to 25% of patients starting ART in some developing countries. Mycobacterium tuberculosis infection accounts probably for one third of the HIV related IRIS events.

Tuberculosis-IRIS (TB-IRIS) represents yet another aspect of the association between HIV and M tuberculosis infection. The TB-IRIS is expected to become a major cause of morbidity during HAART in developing countries, where HIV infection and tuberculosis are endemic and where increasing numbers of patients with advanced symptomatic disease have access to treatment. In clinical practice, the management of IRIS remains problematic due to a lack of clear cut case-definition and the absence of evidence-based prevention and treatment guidelines.

The evaluation of clinical and biological diagnostic tools and therapeutic schemes for the identification, prediction and treatment of TB-IRIS are needed. A better understanding of the immunopathology of TB-IRIS could contribute to define novel predictive markers of TB-IRIS with implication for prevention and diagnostic.

Aim:

To follow-up a cohort of Ugandan HIV-infected patients with and without active M tuberculosis infection in order to:

  • Assess the value of clinical and biological markers of HIV infection and tuberculosis in predicting the occurrence of TB-IRIS
  • Correlate the pathological inflammatory responses of TB-IRIS with incomplete or unbalanced reconstitution of M tuberculosis-specific T regulatory and T effector cells and with inappropriate M tuberculosisinduced activation of monocytes and macrophages.
  • Translate the immunopathological patterns identified into novel and sensitive predictive factors for diagnosis and prevention of TB-IRIS.

Expected results:

The comparison between HIV infected patients with and without TB-IRIS will contribute to an improved definition of TB-IRIS and a better knowledge of its associated morbidity and mortality. Differential patterns of quantitative and functional reconstitution or activation gene expression associated with TB-IRIS will be identified in regulatory T cell, TB-specific effector T cells and activated monocytes/macrophages. The participation of these three possible key player cell types in the physiopathology of TB-IRIS will be better described. New risks factors will be identified among clinical and biological markers with the potential to be used to predict the occurrence of TB-IRIS and facilitate its clinical management.

Potential applications:

The generated results have the potential to be translated into predictive markers of TB-IRIS. Clinical parameters associated with the disease can be readily included by the clinicians into diagnostic algorithms. Patterns of T regulatory-to-T effector cell ratio, TB-antigen T cell recognition and/or cytokines secretion that correlates with the onset of TB-IRIS, can be easily translated into simple flow cytometry, ELISA or ELISPOT diagnostic tests. Monocyte/macrophage activation gene expression related to TB-IRIS may also be used for the development of straight forward molecular diagnostic assays.

Coordinator:

1 - Luc Kestens, PhD
Department of Microbiology
Institute of Tropical Medicine
Nationalestraat 155
2000 Antwerp
Belgium
Tel: 32 3 2476229
Fax: 32 3 2476231
Email: LKestens@itg.be
Website: www.itg.be

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Assoc. Harriet Mayanja-Kizza MBChB, MMed, MS
Makerere University Medical School,
Infectious Disease Institute,
Mulago Hospital Complex
P.O.Box 7072
Mulago Hill Road
Kampala
Uganda
Tel: (+256) 31 307 203
Fax: (+256)41 307 290
Email: hmk@mucwru.or.ug
Website: www.idi-makerere.ac.ug
3Françoise Mascart, MD, PhD Clinic of Immunobiology and Laboratory
of Vaccinology and Mucosal Immunity
Hôpital Erasme
Université Libre de Bruxelles
Campus hospitalo-universitaire d'Anderlecht
ULB CP560, route de Lennik 808,
1070 Bruxelles
Belgium
Tel: (+32) 2 555 34 67
Fax: (+32) 2 555 44 99
Email: fmascart@ulb.ac.be
Website: www.ulb.ac.be/homepage.html
4Peter Reiss, MD, PhD Professor of Medicine
Dept. of Infectious Diseases, Tropical
Medicine and AIDS
P.O. Box 22700
11100 DE AMSTERDAM
The Netherlands
Tel: (+31) 20 566 3321
or (+31) 20 3149300)
Fax: (+31) 20 3149399
Email: p.reiss@amc.uva.nl
5De Baetselier Patrick, PhD Vrije Universiteit Brussel
Laboratory of Cellular and Molecular Immunology
Flanders Interuniversity Institute for Biotechnology
Department of Molecular and Cellular Interactions
Pleinlaan 2
1050 Brussels
Belgium
Tel: (+32) 2 6291979
Fax: (+32) 2 6291981
Email: Patrick.De.Baetselier@imol.vub.ac.be
Website: www.vub.ac.be and www.vib.be
6Camille Locht, PhD INSERM U629
Institut Pasteur de Lille
1, rue du Prof. Calmette
F-59019 Lille Cedex
France
Tel : (+33) 3 20 87 11 51
Fax : (+33) 3 20 87 11 58
Email: camille.locht@pasteur-lille.fr
Website: www.pasteur-lille.fr

 
 
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