Regulation of antiviral immune responses in SIV infection Open Access

Chowdhury, Ankita (2015)

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Human Immunodeficiency Virus (HIV) is still among the most lethal human pathogens, causing 1.6 million deaths this year. Recent progress in understanding the biology of broadly neutralizing antibodies and mechanisms responsible for latent reservoirs has fueled the search for effective HIV vaccine and eradication strategies. The development of vaccine and eradication strategies will require efficient induction of host antiviral responses which requires a better understanding of the immune response to HIV. This thesis elucidates the regulation of antiviral immune responses in the context of Simian Immunodeficiency Virus (SIV) infection of rhesus macaque. First, experimental CD8 T cell depletion led to significantly higher fold increase of virus in blood in controllers compared to progressors (chapter two). While cell-associated virus increased in all CD4 compartments in progressors, it decreased in central memory CD4 T cells in controllers. These results provide strong evidence that CD8 T cells contribute heavily to the suppression of virus in controllers via differential mechanisms in cellular compartments. The next research project led to a detailed analysis of T follicular regulatory (TFR) cells found within germinal centers (GC) that share phenotypic markers with, but are distinct from, T follicular helper (TFH) and T regulatory cells (chapter three). Chronic SIV infection was associated with a decreased TFR to TFH ratio. These data point to the suppressive function of TFR cells and may be one of several mechanisms of immune control within GC with important consequences on the quality of antibody response and on the level of virus replication. Finally, this thesis describes a previously undiscovered aspect of interaction between GC B and T cells resulting in single-celled lymphocytes with surface expression of both T and B cell markers (chapter four). These lymphocytes likely arise as a consequence of membrane exchange following high-affinity interactions and may serve as an additional tool to study vaccine-elicited immune responses within lymph nodes. Taken together, these findings expand on our understanding of the complex CD4 and CD8 T cell responses in the context of SIV infection and may contribute to the development of protective and prophylactic HIV therapeutics.

Table of Contents

List of Tables 3

List of Figures 4

Abstract 1

Chapter One: Introduction 3

Epidemiology 3

Structure and Phylogeny of HIV 4

HIV infection and progression to AIDS 6

Non-human primate models of HIV infection 7

HIV Pathogenesis 8

HIV treatment and cure 10

HIV vaccine development 11

Immune Responses to HIV 15

Chapter Two: Differential impact of in vivo CD8+ T lymphocyte depletion in controller versus progressor SIV-infected macaques. 27

Abstract 27

Introduction 29

Materials and Methods 32

Results 36

Discussion 42

Acknowledgments 47

Figures 48

Chapter Three: Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection 59

Abstract 60

Introduction 61

Materials and Methods 65

Results 71

Discussion 81

Acknowledgements 86

Chapter Four: Identification of single celled lymphocytes with surface expression of T and B cell markers within primate lymph nodes 101

Abstract 102

Introduction 103

Materials and Methods 106

Results 111

Discussion 117

Figures 120

Chapter Five: Discussion 133

References 142

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