Mechanisms of HIV Pathogenesis, Persistence and Control in SIV-infected Rhesus Macaques 公开
Strongin, Zachary (Spring 2023)
Abstract
With over 37 million people infected, HIV remains one of the largest public health burdens worldwide, with a unique ability to continually evade the immune response and persist in a latent viral reservoir despite effective antiretroviral therapy. The ultimate goal of current HIV research is the development of a therapeutic intervention that induces HIV remission in the absence of antiretroviral therapy. In order to further understand mechanisms of HIV pathogenesis, persistence and viral control, we utilized the non-human primate model of HIV infection to investigate target cell populations contributing to pathogenesis and viral persistence, and mechanisms promoting post-treatment and CD8-mediated control of infection.
We identified 7 SIV-infected rhesus macaques that mirrored the human post-treatment controller phenotype and performed immunologic and virologic analysis of blood, lymph node, and colorectal biopsy samples to further understand the characteristics that distinguish them from non-controllers. Overall, lower plasma viremia, reduced cell-associated SIV-DNA, and preserved Th17 homeostasis, including at pre-ART, are the main features associated with sustained viral control after ATI in SIV-infected RMs.
There is a great interest in identifying surface markers on cells that play a role in pathogenesis and persistence to elucidate potential therapeutic targets. We describe CD101-expressing CD4 T cells as an immunosuppressive population that is preferentially depleted following SIV/HIV infection and find that this loss is associated with higher viral burden and increased inflammatory cytokine levels. Furthermore, during long-term antiretroviral therapy, these cells display a phenotypical and functional profile consistent with cells that may critically contribute to reservoir persistence.
HIV cure efforts are increasingly focused on harnessing CD8 T cell functions and better understanding the profile of CD8 T cells promoting HIV control can critically inform novel therapeutic approaches. We explored dynamics of TOX and TCF1 expression in CD8 T cells after SIV infection in lymphoid tissue. CD8 T cells upregulated TOX and differentiated into distinct subsets, including a novel TCF1+CD39+ subset expressing high levels of TOX and inhibitory receptors, but not expressing cytotoxic molecules despite responsiveness to antigen stimulation. Transcriptional analysis of SIV-specific CD8 revealed TCF1+CD39+ cells as an intermediate effector population retaining stem-like features. TOX+TCF1+CD39+ CD8 T cells express higher levels of CXCR5 than terminally-differentiated cells and were found at higher frequency in follicular micro-environments. Importantly, their levels were strongly associated with viral control and lower reservoir size. Collectively, these data describe a unique population of lymphoid CD8 T cells possessing both stem-like and effector properties that contribute to limiting SIV persistence.
Taken together, these studies highlight potential pathways to target in the design of future therapeutic interventions to achieve an HIV cure.
Table of Contents
Chapter One: Introduction ..................................................................................................... 1 The HIV Pandemic............................................................................................................................ 1 HIV Infection, Transmission and Life Cycle ....................................................................................... 1 HIV Pathogenesis ............................................................................................................................. 3 Innate Immune Response to HIV ...................................................................................................... 4 Adaptive Immune Response to HIV .................................................................................................. 5 Antiretroviral Therapy ..................................................................................................................... 8 The HIV reservoir ........................................................................................................................... 10 Chronic infection and CD8 T cell exhaustion ................................................................................... 13 CD8 T cell Exhaustion in HIV infection ............................................................................................ 16 HIV Cure ........................................................................................................................................ 18 Animal models of HIV infection...................................................................................................... 22 Chapter One Summary................................................................................................................... 25
Chapter Two: Virologic and immunologic features of SIV control post-ART interruption in rhesus macaques .................................................................................................................. 26
Abstract ......................................................................................................................................... 27 Introduction................................................................................................................................... 28 Results........................................................................................................................................... 30 Discussion...................................................................................................................................... 37 Materials and Methods.................................................................................................................. 43 Chapter Two Figures ...................................................................................................................... 48
Chapter Three: The role of CD101-expressing CD4 T cells in HIV/SIV pathogenesis and persistence............................................................................................................................ 59
Abstract ......................................................................................................................................... 60 Introduction................................................................................................................................... 62 Results........................................................................................................................................... 64 Discussion...................................................................................................................................... 72 Materials and Methods.................................................................................................................. 77 Chapter Three Figures .................................................................................................................... 86
Chapter Four:
Distinct SIV-specific lymphoid tissue CD8 T cells simultaneously exhibit
effector and stem-like profiles and associate with viral control and reduced reservoir size
Abstract ....................................................................................................................................... 105 Introduction................................................................................................................................. 106 Results......................................................................................................................................... 108 Discussion.................................................................................................................................... 117 Materials and Methods................................................................................................................ 124 Chapter Four Figures.................................................................................................................... 130
Chapter Five: Discussion ....................................................................................................155 References ...........................................................................................................................161
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