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Role of Environmental Immune Instruction in Dendritic Cell-mediated HIV-1 trans-infection

Bothwell, Emily Grace (2024) Role of Environmental Immune Instruction in Dendritic Cell-mediated HIV-1 trans-infection. Master's Thesis, University of Pittsburgh. (Unpublished)

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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 Unpublished results from our group show that monocyte derived DC matured under type-1 polarizing conditions (MDC1), either through exposure to activated autologous CTL or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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Bothwell, Emily Graceegb32@pitt.eduegb32
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMailliard, Robbie Brbm19@pitt.edurbm19
Committee MemberCastanha, Priscilapmd35@pitt.edupmd35
Committee MemberMattila, Joshua Tjmattila@pitt.edujmattila
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


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