Regulation of HIV latency dynamics in monocytes and monocyte-derived macrophages

Blanco, Alexandra V.

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https://hdl.handle.net/2142/124330 Copy

Description

Title

Regulation of HIV latency dynamics in monocytes and monocyte-derived macrophages

Author(s)

Blanco, Alexandra V.

Issue Date

2024-04-24

Director of Research (if dissertation) or Advisor (if thesis)

Kieffer, Collin

Doctoral Committee Chair(s)

Kieffer, Collin

Committee Member(s)

• Sirk, Shannon
• Underhill, Gregory
• Harley, Brendan

Department of Study

Bioengineering

Discipline

Bioengineering

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• HIV
• HIV latency
• monocytes
• macrophages
• T-cells
• virology

Abstract

The development of antiretroviral therapy (ART) greatly improved the clinical outcome for people living with human immunodeficiency virus (HIV) infection. However, upon cessation of ART, a pool of cells harboring non-productive or latent infections can spontaneously reactivate to produce virus and lead to rebound viremia. These cells form stable and long-lived latent HIV reservoirs, and constitute a major hurdle to eradicating HIV. To achieve full control of HIV replication in the body, eradication strategies that consider all cellular reservoirs must be developed. Cure-based efforts have mainly focused on targeting the latent HIV reservoir in CD4+ T-cells, the primary cellular targets of HIV infection. However, myeloid cells like monocytes and macrophages constitute a clinically relevant reservoir given their potential for trafficking and spreading virus between tissues. Despite posing a great threat for viral dissemination, the monocyte and macrophage latent HIV reservoir remains understudied and poorly represented in cure-based efforts. Therefore, this thesis aims to study the dynamics of HIV latency regulation within monocytes and macrophages to guide the development of successful HIV eradication strategies for all host cell types. The central hypothesis of this thesis proposes that the regulation of HIV latency will vary between T-cells, monocytes, and macrophages, and will be altered in response to signals directing macrophage differentiation, polarization, and function. Here, we develop in vitro monocyte and monocyte-derived macrophage (MDM) models of HIV latency to characterize HIV latency regulation in the context of biological function and therapy. We discover that macrophage differentiation triggers HIV reactivation and identify cell-type specific differences in response to HIV latency modulating agents. Altogether, this thesis will improve our understanding of the HIV latent reservoir and will elucidate different mechanisms by which latency is regulated in myeloid cells, providing a foundation for the development of effective latency modulating strategies.

Graduation Semester

2024-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2024 Alexandra Blanco

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