Bothwell, Emily Grace
(2024)
Role of Environmental Immune Instruction in Dendritic Cell-mediated HIV-1 trans-infection.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
The HIV-1 latent reservoir that persists despite antiretroviral therapy continues to be a challenge in finding a functional cure. Dendritic cells (DC) are known to facilitate HIV-1 trans-infection of CD4+ T cells, a process considerably more efficient than direct, cell-free infection. Thus, DC are thought to play a critical role in the establishment and size of the latent reservoir. HIV exploits the trans-infection process via modulation of the immune microenvironment and DC function. Unpublished results from our group show that monocyte derived DC matured under type-1 polarizing conditions (MDC1), either through exposure to activated autologous CTL or soluble mediators of type-1 immunity, more efficiently mediate HIV-1 trans-infection as compared to DC matured in the presence of PGE-2 (MDC2), a mediator of chronic inflammation and inhibitor of type-1 immunity. The T helper signal CD40L was also implicated in contributing to the enhanced trans-infection by MDC1. In this study, we demonstrate that MDC1 exhibit a selective increase in Siglec-1 expression, enabling enhanced virion binding and subsequent trans-infection. Using single-cell RNA-seq analysis on MDC1 and MDC2, we discovered differential mRNA transcription of various factors uniquely induced by CD40L signaling, including the chemokine CCL20. We confirmed CD40L-induced CCL20 protein release by MDC1 and demonstrated that when exposed to this MDC1-associated factor, susceptibility of CD4+ T cells to HIV-1 infection was increased. Overall, our study demonstrates that environmental immune instruction greatly influences the ability of mature DC to facilitate HIV-1 trans-infection, where a combination of pro-inflammatory signals induce a type-1 DC with functions owing to efficient trans-infection while signals inhibiting type-1 immunity produce a type-2 DC with diminished trans-infection ability.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Bothwell, Emily Grace | egb32@pitt.edu | egb32 | |
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| ETD Committee: |
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| Date: |
16 May 2024 |
| Date Type: |
Publication |
| Defense Date: |
5 April 2024 |
| Approval Date: |
16 May 2024 |
| Submission Date: |
16 April 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
47 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
DC, CTL, HIV-1, trans-infection |
| Date Deposited: |
16 May 2024 20:19 |
| Last Modified: |
16 May 2024 20:19 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46124 |
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