| dc.description.abstract | Human Immunodeficiency Virus (HIV) continues to be an overwhelming challenge in both global health and immunology. With no cure available, 30 million people worldwide rely on antiretroviral therapy (ART) to prevent transmission and disease progression. However, individuals on ART are at elevated risk for numerous comorbidities and are susceptible to continued disease progression should treatment be stopped or interrupted. Addressing the challenges resulting from treatment and lack of cure requires a deeper understanding of the complex underlying immunology of HIV infection, treatment, and therapeutics.
Single-cell RNA sequencing (scRNAseq) is continually advancing our understanding of immune dynamics and when combined with well-characterized rhesus macaque models of HIV, provides an opportunity to profile immune perturbations over extensive time courses in a controlled setting. In this thesis, I present two studies that further our understanding of the host immune response across stages of infection, treatment, and therapeutic intervention, using rhesus macaque models.
In the first study (Chapter 2), I comprehensively profiled immune dynamics during untreated infection, ART initiation, and long-term ART, leveraging a longitudinal cohort of SIV-infected (Simian Immunodeficiency Virus) macaques. This work is particularly relevant given the increasing age and average time spend on ART among people living with HIV. scRNAseq revealed key immune shifts during acute and chronic infection, as well as over five years of subsequent ART. I identified cell type composition shifts during prolonged untreated infection and uncovered areas of unresolved immune dysregulation despite long-term ART– most prominently among myeloid gene expression and enrichment. I further link transcriptional changes to intact proviral burden and identified ribosomal pathways as markers infection stage, treatment status, reservoir size. Finally, by evaluating published immune correlates of treatment outcome, I identify nuances in signatures changing and remaining stable with time on ART.
In the second study (Chapter 3), I expand on the baseline infection and treatment case by evaluating immune dynamics in response to a post-exposure combination therapeutic (Ad26/MVA + PGT121 + Vesatolimod) previously shown to induce post-ART viral control in most (7/10) treated macaques with Simian Human Immunodeficiency Virus (SHIV). Here I identify features of therapeutic response and implicate a previously defined Antibody-Dependent Cellular Phagocytosis signature as being associated with control. Furthermore, I identify a new cytotoxic transcriptional module in T and NK cells associated with both non-rebounding animals and post-rebound controller animals, suggesting a shared effector program associated with successful virologic control.
Supported by a thorough introduction on immunological techniques, questions and applications to HIV studies (Chapter 1), and a discussion of intersectionality and future directions of the field (Chapter 4), this thesis provides a comprehensive analysis of immune dynamics across the lifecycle of viral infection, treatment, and therapeutic intervention in macaque models of HIV. This work demonstrates how the host immune environment influences therapeutic success, laying a foundation for future therapeutic design. | |
