ORCID ID
Graduation Date
Summer 8-15-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Pharmaceutical Sciences
First Advisor
Howard S Fox
Abstract
Human immunodeficiency virus type 1 (HIV-1) is an enveloped retrovirus that significantly impairs the human immune system. A common complication of HIV-1 infection is HIV-associated neurocognitive disorder (HAND), which, prior to the introduction of antiretroviral therapy (ART), led to considerable morbidity and mortality due to untreated neuropsychiatric manifestations. Although ART has substantially reduced the incidence of HIV-associated dementia (HAD), approximately 50% of people living with HIV (PLWH) continue to experience milder forms of HAND. The CNS is seeded by HIV during the acute phase of infection. Once in the brain, HIV targets and activates resident immune cells, primarily microglia and CNS-associated macrophages (CAMs), leading to sustained neuroinflammation and neuronal damage. These myeloid cells also act as viral reservoirs, contributing to the persistence of infection. Despite decades of research, the mechanisms of immune activation within the brain across different stages of HIV infection remain incompletely understood.
This dissertation addresses these knowledge gaps by delineating transcriptomic and epigenomic alterations in brain immune cells during the course of infection, utilizing next-generation sequencing (NGS) technologies in a simian immunodeficiency virus (SIV) infected rhesus macaque model.
Chapter 1 provides a comprehensive introduction, covering the epidemiology and cellular mechanisms of HIV and HAND, the clinical landscape of HAND under cART and in the context of drug abuse, animal models for HAND research, and the application of NGS technologies to study HAND at the transcriptomic and epigenomic levels.
Chapter 2 employs single-cell RNA sequencing (scRNA-seq) to characterize brain myeloid cell responses during acute SIV infection. The key phenotypes that exhibited transcriptional signatures linked to neurodegenerative disorders were identified and validated through IHC staining. Additional genes that were globally upregulated in brain myeloid cells in acute SIV infection have been associated with inflammatory signaling and cellular senescence.
Chapter 3 focuses on lymphocyte dynamics in the brain during acute SIV infection. Significant shifts in T cell phenotypes were observed, notably the loss of CD4+ memory T cells and expansion of proliferating cytotoxic CD4+ T cells, which expressed high levels of viral entry receptors (CD4, CCR5) and adhesion molecules (LFA-1, VLA-4). The cytotoxic CD4+ T cells harbored the highest SIV infection burden in the brain, implicating them as "Trojan horse" vectors for CNS infection. Collectively, this chapter offers a detailed transcriptomic landscape of lymphocytes and identifies phenotypes that may facilitate early viral dissemination into the CNS.
Chapter 4 characterizes brain myeloid cell phenotypes in chronic SIV infection and encephalitis (SIVE) using multiomic sequencing that integrates single-nucleus RNA-seq (snRNA-seq) and ATAC-seq (snATAC-seq). Two distinct myeloid phenotypes were identified in SIVE brains. Detection of a substantial number of SIV-positive cells and SIV DNA fragments helped the understanding of virus reservoir in brain myeloid cells. More SIV DNA at the long terminal repeat (LTR) regions was enriched near the FSTL5 gene of the host genome. The LTR region was also found to be enriched with host transcription factor (e.g. Sp1, NF-κB, NFAT) binding motifs, which further highlight virus-host interactions.
Chapter 5 explores the combined impact of SIV infection, morphine use, and cART on brain myeloid cells using multiomic approaches. Results show that cART restores myeloid cell homeostasis during infection, consistent with observations in HIV-infected individuals. However, integrative analyses of human and macaque data revealed a higher prevalence of activated/inflammatory phenotypes in human samples under cART. Morphine use was found to be associated with immunosuppressive effects in brain myeloid cells, including decreased expression of MHC class II and interferon-inducible genes. These findings enhance the understanding of the complex interactions between HIV/SIV infection, opioid exposure, and ART in shaping CNS immunity.
Recommended Citation
Xu, Xiaoke, "Transcriptomic and Epigenomic Profiling of Immune Cells Responses to Simian Immunodeficiency Virus Infection in the Brain" (2025). Theses & Dissertations. 971.
https://digitalcommons.unmc.edu/etd/971
Included in
Medical Genetics Commons, Medical Immunology Commons, Medical Neurobiology Commons, Neurosciences Commons, Viruses Commons
Comments
2025 Copyright, the authors