Date of Award

2019

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Julie Westerink

Second Advisor

Wei Jiang

Third Advisor

Laura Kasman

Fourth Advisor

Eric Meissner

Fifth Advisor

Betty Tsao

Abstract

The introduction of antiretroviral therapy has significantly reduced HIV-related morbidity and mortality and transformed HIV infection into a chronic disease. Consequently, the life expectancy of HIV-positive individuals considerably improved leading to a rapid growth of the aging HIV-positive population. Together, advanced age and HIV infection increase susceptibility to potentially deadly infections caused by Streptococcus pneumoniae. Despite preventative approaches, such as pneumococcal vaccination, it remains a challenge to induce potent and durable immune responses against pneumococcal polysaccharides in HIV-positive persons and invasive pneumococcal disease rates remain 35-fold higher as compared to healthy individuals. Poor responses to vaccine antigens in HIV+ individuals are at least in part, related to intrinsic B cells defects. Herein, we investigated the potential mechanisms of impaired vaccine responses in aging HIV+ individuals. First, we measured quantitative and qualitative antibody responses in young and aging HIV+ individuals as compared to age-matched HIV- controls. We found that similarly to aging HIV- persons, both young and aging HIV+ persons have significantly reduced antibody production and functionality as compared to young HIV- individuals. Interestingly, we found that there are profound race-related differences in functional antibody response to pneumococcal vaccination in HIV-infected individuals regardless of age. Next, we assessed the molecular signals that may influence diminished responses to pneumococcal vaccination in the aging HIV+. This assessment revealed, that there is a correlation between high levels of expression of pro-inflammatory cytokine IP-10 and functional antibody titers in aging HIV+ population. To further probe mechanisms of impaired vaccine responses, we examined the phenotype, individual cellular changes and inter-cellular gene expression that shape polysaccharide-specific B cell responses by utilizing flow cytometry and single cell genomics approaches. We showed the phenotype of polysaccharide specific B cells changes with age from predominantly IgM-memory (CD27+IgM+) to switched memory (CD27+IgM-) in HIV-negative individuals. However, in HIV+ individuals there is no age-related shift. Furthermore, aging HIV+ displayed a phenotype similar to young HIV- individuals but in significantly reduced percentages. Single cell genomic studies of pre-immunization and post-immunization IgM memory B cells demonstrated significant heterogeneity and identified two distinct cellular subpopulations of IgM memory that were found in both HIV+ and HIV- persons. A subpopulation of IgM memory B cells with high levels of expression of CD80, BAFF-R, TACI, and TCF3 is speculated to play a dominant role in a production of robust immune response to PPS-antigens. It was more frequently observed in healthy young adults and in aging HIV+ individuals. However, despite higher prevalence of this subpopulation in aging HIV+ group pre- and post-immunization, the absolute number of IgM B cells was very low and potentially had a more significant impact on the ability to respond to TI-2 antigens. These data suggest that both heterogeneity and low absolute number of IgM memory B cells play an important role in impaired pneumococcal vaccine responses. In conclusion, our study demonstrated that the immune response to pneumococcal vaccination in aging HIV-positive individuals is influenced by multiple factors including HIV infection, age, race, levels of inflammation, and phenotype of IgM memory B cells. Therefore, improved understanding of intrinsic B cell defects in HIV+ population is necessary in order to identify new potential adjuvant targets for use in future vaccine formulations.

Rights

All rights reserved. Copyright is held by the author.

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