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Viral infections in immunocompromised hosts

Thursday 17 January 2013

Dr. Debbie van Baarle

Research performed in the group of Dr D van Baarle focuses on anti-viral T-cell immunity and involves analysis of kinetics and characterization of virus-specific T cells, including human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV6) and hepatitis C virus (HCV) in relation to viral dynamics and disease progression. These studies are aimed to provide insight in the determinants of protective immunity.

Viral hepatitis
As Hepatitis C Virus (HCV)-infection is an increasing problem, especially in the HIV-setting, we study host factors that predict spontaneous clearance, the impact of HIV-infection and the influence of therapy on HCV-specific T-cell responses within the Amsterdam Cohort Studies (in collaboration with Dr M Prins, GGD Amsterdam) and clinical trials (UMCUtrecht). Next to the magnitude and breadth of HCV-specific T cell responses, we are studying the impact of manipulation of these responses ex vivo. One of the current projects focuses on viral escape from the HCV-specific T cell response. By analyzing virus sequences from patients, we will determine the amount of immune escape and consequences for specific immune responses and disease outcome.

Reconstitution of antigen-specific T cells after SCT
In the Stem cell transplantation (SCT) setting we study reconstitution of CD4+ and CD8+ T cells directed against latent herpesvirus like EBV and CMV, which can reactivate after SCT and lead to severe disease.(Grant from Dutch Cancer Society) This will provide more insight into the regulatory aspects of herpesvirus-specific T cells and antigen-specific reconstitution of the immune system and may lead to improved diagnostic tools and/or a rational choice for treatment or prevention. In children we initially focus on HHV6-specific T-cell immunity, a herpesvirus which specifically reactivates at an early stage after SCT in children. (collaboration with Dr JJ Boelens) Currently we are studying the role of different cytolytic effector molecules by which T cells can kill potential target cells and the role of these molecules in control of viral reactivation.

Specific T cell immunity and protection through HLA-alleles
In collaboration with Jose Borghans, the role of the protective HLA-alleles HLA-B27 and B57 in delayed HIV-disease progression is studied. On the one hand T-cell specific features are analyzed to see whether HLA-B57/B27-restricted T cells are more powerful in responding to the virus. On the other hand viral sequences are analyzed to investigate whether the virus has changed within an individual as well as at a population level due to immune pressure and whether this has consequences for immune recognition.

In line with this, the role of HLA-B molecules in general is studied in detail in a collaboration with Dr. C. Kesmir to elucidate why the two main HLA class I alleles, A and B, have a differential effect with respect to resistance to infectious diseases and immunodominance of T-cell responses. Both at the level of antigen presentation as well as the level of T-cell recognition, HLA-A and B-responses are studied. Using a multi-disciplinary approach combining experimental and theoretical analyses the aim is to explain why HLA-B responses are protective and dominant, and thereby provide new insight in how host genetics shape the immune response to pathogens.(UU High-potential grant) Currently, we are studying the T cell receptor repertoire of virus-infected patients to determine the implications of a broad versus a narrow TCR repertoire with respect to viral disease outcome and viral mutations.

Techniques
Cell separation techniques, Q-PCR, culure, FACS-analysis, elispot-assay

Duration
6 or 9 months

Contact
Dr. Debbie van Baarle, d.vanbaarle@umcutrecht.nl, 088 755 539 46
Dr. Kristin Denzer, k.denzer@umcutrecht.nl, 088 75 643 68

More info
Website UMC Utrecht - Dept. of Immunology

Key Publications
High level of perforin expression in T cells: An early prognostic marker of the severity of herpesvirus reactivation after allogeneic stem cell transplantation in adults.
Pietersma FL, van Dorp S, Jacobi R, Ran L, Nanlohy NM, Schuurman R, Minnema MC, Meijer E, van Baarle D
Clin Infect Dis. 2010 Mar 1;50(5):717-25.

A comparative study of HLA binding affinity and ligand diversity: implications for generating immunodominant CD8+ T cell responses.
Rao X, Costa AI, van Baarle D, Kesmir C
J Immunol. 2009 Feb 1;182(3):1526-32.

HCV-specific T-cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance.
Ruys TA, Nanlohy NM, van den Berg CH, Hassink E, Beld M, van de Laar T, Bruisten S, Wit F, Krol A, Prins M, Lange J, van Baarle D
J Viral Hepat. 2008 Jun;15(6):409-20.

Tight regulation of the EBV-setpoint: Inter-individual differences in EBV DNA load are conserved after HIV-infection.
Piriou E, van Dort K, Otto SA, van Oers MH and van Baarle D.
Clinical Infectious Diseases 2008, Jan15; 46(2):313-6

Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin Lymphoma.
Piriou E, van Dort K, Nanlohy NM, van Oers MH, Miedema F, van Baarle D.
Blood 2005; Nov 1;106(9):3166-74

Failing immune control due to impaired CD8+ T cell maturation: CD27 may provide a clue.
D. van Baarle, S. Kostense, M. H. J. Van Oers, D. Hamann, and F. Miedema.
Trends Immunol 23, 2002: 586-591

Dysfunctional Epstein-Barr virus (EBV)-specific CD8(+) T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma
van Baarle D., E. Hovenkamp, M. J. Kersten, M. R. Klein, F. Miedema, and M. H. van Oers.
Blood 2001; 98:146-155

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