Advisory Committee Chair
Laurie F Harrington
Advisory Committee Members
Paul A Goepfert
Sonya Heath
Christina Ochsenbauer
Chander Raman
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
CD4+ T cells, often referred to as helper T cells, play a crucial role in the formation of antiviral immune responses following infection and vaccination. However, this can be disrupted by various forms of immune dysregulation. Many groups have described how HIV-1 adaptation and immune escape can lead to dysregulated HIV-specific immune responses. Our lab has previously shown that predicted HLA-II associated HIV-1 adaptation leads to dysregulated, poorly immunogenic CD4+ T cell responses in HIV-1 infection. Here, we focus on the impact of this HLA-II associated viral adaptation in the setting of HIV-1 vaccination. We show that HLA-II associated, vaccine-matched adapted epitopes (AE) elicit less CD4+ T cell responses than their non-adapted epitope (NAE) counterparts. Additionally, we show that the CD4+ T cell response magnitude to NAE, but not AE, correlates with Env-specific antibody production. These findings show that HLA-II associated HIV-1 adaptation weakens CD4+ T cell responses in HIV-1 vaccine recipients, and suggests that vaccinating with a fully non-adapted HIV-1 immunogen sequence would provide the best chance at achieving effective protection against HIV-1 infection. Immune dysregulation occurs in response to other viruses as well. At the start of the COVID-19 pandemic, very little was known about the SARS-CoV-2 host response. As shown here, our group was one of the first to identify that the immune iv system is dysregulated following SARS-CoV-2 infection, not only in those with severe symptoms, but also in those with moderate/mild COVID-19. This immune dysregulation included increased expression of activation and exhaustion markers on multiple immune cells including CD4+ T cells, CD8+ T cells, and B cells. In a follow-up project, our group investigated the impact of this immune dysregulation in a cohort of individuals experiencing prolonged duration of symptoms following COVID-19 infection, also known as post-acute sequalae of COVID-19 (PASC) or long COVID. Although we did not observe any differences between immune activation/exhaustion, our group did find that PASC patients had sustained SARSCoV- 2-specific responses compared to those with resolved COVID-19. These findings strongly suggest that at least a subset of PASC patients exhibit persistent exposure to viral antigens, providing important information into the etiology of PASC. In summary, our findings show that immune dysregulation can impact virus-specific T cell responses. Identifying and accounting for this immune dysregulation could prove to be beneficial when identifying optimal vaccine strategies or new therapeutic targets.
Recommended Citation
Files, Jacob K., "Determining the Impact of Immune Dysregulation on CD4 T Cell Responses to HIV-1 and SARS-COV-2" (2022). All ETDs from UAB. 486.
https://digitalcommons.library.uab.edu/etd-collection/486