Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Laurence C. Eisenlohr

Abstract

HIV-1-specific CD4+ T cells (TCD4+) play a critical role in controlling HIV-1 infection. Robust HIV-1-specific TCD4+ responses are associated with decreased viral load and increased antibody neutralization breadth, and thus understanding the processes that lead to successful HIV-1-specific TCD4+ activation is crucial. According to convention, TCD4+ activation is mediated by professional antigen-presenting cells (APCs), such as dendritic cells (DCs), macrophages, and B cells that: 1) take up extracellular antigen, such as whole virions, 2) proteolyze internalized virions into smaller peptides within the endocytic compartment, 3) load resulting peptides onto major histocompatibility complex class II (MHCII) molecules within the late endosome, and 4) transport the peptide:MHCII complexes to the plasma membrane, where they can provide activating signal to antigen-specific TCD4+. However, several alternative processing modes have been described. Endogenous processing, one of these alternatives, occurs when the APC becomes productively infected and nascent viral proteins are used as processing substrates for presentation on MHCII. However, the relative contributions of these pathways to the HIV-1-specific TCD4+ response are unknown. In addition, the cell types capable of MHCII-restricted presentation may be more complex than originally appreciated. Notably, TCD4+, which express MHCII upon activation and are HIV-1 host cells, might act as APCs during an HIV-1 infection. In this study, I used a lentiviral transduction system to achieve HIV-1-specificity in primary human TCD4+. I then assessed the ability of primary monocyte-derived DCs and activated TCD4+ to present HIV-1-derived antigen. I show that activated TCD4+ are highly effective at MHCII-restricted presentation of an immunodominant HIV-1-derived epitope due to the tropism of HIV-1 for TCD4+ and the efficiency of endogenous processing. Additionally, and unexpectedly, I found that MHCII-restricted TCD4+-to-TCD4+ presentation facilitates transfer of virus to HIV-1-specific TCD4+, providing both a potential explanation for the rapid spread of the virus to HIV-1-specific TCD4+ in vivo and a novel mechanism for compromising the host response.

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