The effect of chronic HIV-1 infection on circulating B cells and peripheral T follicular helper cells

Abstract

This thesis advances our understanding of circulating B and pTFH cells in untreated chronic HIV+ infection. My studies determined the frequency, phenotype, and functional response to antigen stimulation of pTFH and B cells in chronically infected HIV+ individuals. I found that while B cells were activated at baseline and had high PD-1 expression, antigen responses were improved with CD4+ T cell help and PD-1 blockade. pTFH cells, the best providers of B cell help, had decreased maximal responses to stimulation as measured by expression of CD40L and ICOS, but maintained responses to recall antigens. The fact that decreased maximal responses did not correlate with any clinical aspects of disease could suggest that pTFH cell dysfunction may occur early in HIV infection. Functional pTFH cell responses to recall antigen existed in HIV+ individuals but also did not correlate with clinical aspects of disease. This maintenance of HIV-specific pTFH cells may simply be a result of HIV viremia driving chronic immune activation. However, the existence of recall tetanus responses suggests that vaccines that elicit protective antibodies may still be effective in HIV+ individuals. Thus, for vaccines designed to elicit antibody responses, adjuvants to optimize TFH cell help may be advantageous. Additionally, pTFH cells should be investigated for a potential role identifying immune correlates of vaccination. As a final component of my thesis, I compared a new technology, mass cytometry, to the current standard technology in the field, fluorescence cytometry, and found they were highly comparable. My results demonstrated that multidimensional analysis combined with flow cytometry will be particularly useful for the comprehensive characterization of cells, including cells with dynamic or unexpected cell phenotypes in health and disease.