Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Michael R. Betts

Abstract

Since its initial documentation in 1981, the acquired immunodeficiency syndrome (AIDS) epidemic has impacted more than 70 million people. As the causative agent of AIDS, human immunodeficiency virus (HIV) is a retrovirus that integrates a copy of its viral genome (termed provirus) into the genome of target cells known as CD4+ T cells. With antiretroviral therapy (ART), persons living with HIV (PLWH) can suppress viral replication and prevent progression to AIDS. However, ART is usually a lifelong requirement as interruption can lead to viral rebound via transcription at the integrated viral genome. During early HIV infection, some infected cells can enter a quiescent state that results in a state of infection known as latency. Persistent infection and reversible latency are characteristics of the HIV reservoir. As a result, there is no universally accessible cure for HIV. A functional cure of HIV – which is to suppress viral replication without ART – is a primary goal of HIV cure research. Such a strategy requires an in-depth understanding of the HIV reservoir but many CD4+ T cells, each with different function and phenotype, contribute to the collective HIV reservoir that is located throughout different tissue environments. To address this challenge, this study deciphers the reservoir through the lens of tissue versus blood compartmentalization at a subset resolution to address the impact of residency and circulation as well as with a novel single-cell approach to enable a comprehensive analysis of the HIV reservoir during ART. While the characteristics of integration were generally the same across compartments, there was a lack of overlap between tissues and blood to suggest the existence of sub-reservoirs where there may be unique reservoirs based on residency status. Furthermore, the single-cell profiling revealed extensive heterogeneity between and within individuals with some infected cells displaying a poised signature for reactivation. These results provided a clearer picture of the HIV reservoir to come closer to the goal of a functional cure that can effectively target latency across the location and phenotypic diversity of the HIV reservoir.

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