Buyck, H.C.E.; (2008) Virological and immunological studies of human cytomegalovirus infection in allogeneic stem cell transplant recipients. Doctoral thesis , University of London.

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Abstract

Human cytomegalovirus (HCMV) is the most common viral infection complicating stem cell transplantation, and if untreated frequently results in a fatal outcome. In order to identify the main risk factors for HCMV infection, a retrospective study of all allogeneic stem cell transplants performed over a five year period at a single centre was undertaken. The main risk factors for HCMV infection following transplantation were identified as a HCMV seropositive donor and/or recipient and in-vivo use of the monoclonal antibody, anti-CD52 (alemtuzumab). A prospective study of HCMV viral loads determined by real time PCR using a Taqman probe was undertaken, and the viral load dynamics of 57 patients were analysed. Despite the use of aciclovir prophylaxis, PCR monitoring and pre-emptive therapy, the peak viral load, viral replication rate and the total duration of viraemia remain significant risk factors for symptomatic HCMV infection. Peak viral load was the most significant predictor of time to viral clearance. A prospective longtitudinal study of the reconstitution of the HCMV specific immune response following allogeneic stem cell transplantation was performed in 20 patients using intracellular interferon gamma staining and flow cytometry. HCMV infection was associated with a significantly reduced HCMV specific CD4+ T cell response. Furthermore, in patients receiving in-vivo anti-CD52, HCMV specific CD4+ T cell immune recovery was significantly delayed. An HLA class II epitope mapping study was undertaken in stem cell transplant recipients and healthy controls using peptide pools consisting of 15 mer overlapping peptides spanning the entire amino acid sequence of the HCMV proteins, pp65 and IE1. Using intracellular cytokine detection in CD4+ T cells, a number of novel HCMV specific class II epitopes were identified. Transplant recipients responded to a broader range of epitopes than HCMV seropositive controls. These results have important implications for HCMV specific immunotherapy in allogeneic stem cell transplantation.

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