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Title: Investigation of B cell subsets and vaccination responses in HIV-1 infection and CVID
Author: Hart, Melanie Sarah
ISNI:       0000 0004 2715 2653
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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The contribution of intrinsic defects in B and/or T cell function or impaired T-B cell interaction towards poor recall and neo-antigen vaccine responses in HIV-1 infection are not fully understood. Using CVID as a model for B cell maturation, we show patients with untreated HIV-1 infection have increased transitional and tissue like B cells and reduced IgM memory and class switched memory B cell proportions. Loss of IgM memory B cells is associated with progressive HIV-1. Antiretroviral therapy reduces transitional and tissue like B cell percentages but does not restore IgM memory or class switched memory proportions. Most HIV-1 patients on ART have reduced antibody levels post tetanus and pneumococcal vaccination. IgM memory B cell depletion associates with poor post vaccine IgM pneumococcal titres in HIV-1 suggesting loss of IgM memory B cells may be a risk factor for invasive pneumococcal disease. CVID patients with lung disease had lower memory B cells and a trend towards a loss of IgM memory B cells. IgM memory B cell percentages were protective against bronchiectasis in CVID patients displaying extremely low class switched B cell percentages. Evaluation of proteins implicated in the pathogenesis of PID, autoimmunity and malignancy, showed increased expression of BAFF and APRIL in CVID and untreated HIV-1 and normalisation by ART. BAFF upregulation was associated with CD4 T cell decline without treatment. Expression of BAFF and APRIL ligands demonstrated decreased BAFF-R on class switched memory B cells in HIV-1 and increased TACI on tissue like and memory B cells. A loss of follicular helper T cells in untreated HIV-1 infection was reported, however this was not a selective depletion and numbers were normalised by ART. In conclusion, we identify multiple novel defects in B cell composition in HIV-1 and suggest these may have implications for the design of effective vaccination strategies.
Supervisor: Kelleher, William ; Henderson, Don Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral