All ETDs from UAB

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.

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