Investigating the contribution of CD4+ T cell subsets to SIV disease progression and persistence Público

McGary, Colleen Shannon (2016)

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CD4+ T-cells are progressively depleted from the blood and mucosa of individuals infected with Human Immunodeficiency Virus-1 (HIV), resulting in a massive disruption of T-cell homeostasis. The severity of HIV infection is coupled not only to the magnitude but also to the quality of CD4+ T-cells lost. Moreover, a small subset of infected CD4+ T-cells persists during antiretroviral therapy (ART), constituting the latent viral reservoir and the major barrier to an HIV cure. Determining the phenotypic and functional profile of virally infected CD4+ T-cells is critical for designing effective HIV therapeutic interventions. To investigate which CD4+ T-cell subsets contribute to HIV pathogenesis, we utilized the pathogenic and non-pathogenic Simian Immunodeficiency Virus (SIV) infection models of rhesus macaques (RMs) and sooty mangabeys (SMs), respectively, and first examined how the preferential infection of central memory (TCM) CD4+ T-cells affects CD4+ T-cell homeostasis. Increased proliferation of CD4+ TCM cells was found only in SIV-infected RMs, yet was unable to restore CD4+ T-cell homeostasis, demonstrating how aberrant TCM proliferation facilitates disease progression. We then examined the impact of anatomic localization of CD4+ T-cells by investigating the loss of circulating CCR6+ and CD161+ CD4+ T-cells during SIV infection. While CD161+CCR6-CD4+ T-cells were preferentially infected, we found that CCR6+CD4+ T-cells accumulated in the gut mucosa of SIV-infected RMs, but not in SMs, demonstrating how these alterations are damaging to the host and advance disease progression. Finally, to investigate the immunophenotype of latently infected cells, we examined ART-suppressed, SIV-infected RMs and identified CTLA-4 and PD-1-expressing cells as the major contributors to the viral reservoir across multiple anatomic sites. Importantly, we showed, for the first time, that CTLA-4+PD-1- regulatory T-cell-like (Treg) CD4+ T-cells contained the highest SIV-DNA levels, harbored replication competent virus, and localized outside the follicle in the T-cell zone. These data illustrate how SIV establishes and maintains viral persistence by targeting Tregs and follicular helper T-cells, two subsets critical for immune function. Taken together, these findings identified CD4+ T-cell subsets critical for HIV/SIV pathogenesis and persistence, and ultimately, will provide insight into designing therapeutics aimed at restoring CD4+ T-cell homeostasis and achieving a functional cure.

Table of Contents

Chapter One: Introduction 1

HIV Epidemiology and Origins 1

HIV Biology 2

HIV Transmission and Dissemination 4

Kinetics of Immune Response 6

HIV Pathogenesis 9

Animal Models for HIV-1 Infection 12

CD4+ T cell selection and depletion 14

Memory CD4+ T cells 15

Functional CD4+ T cell subsets 18

Anatomic Characterization of CD4+ T cells 23

Antiretroviral therapy (ART) and the treatment of HIV 25

Limitations of ART 28

HIV Reservoir 30

Summary 34

Chapter Two: Increased stability and limited proliferation of CD4+ central memory T cells differentiate nonprogressive simian immunodeficiency virus (SIV) infection of sooty mangabeys from progressive SIV infection of rhesus macaques 36

Abstract 37

Introduction 38

Materials and Methods 41

Results 43

Discussion 50

Figures 55

Chapter Three: The loss of CCR6+ and CD161+ CD4+ T cell homeostasis contributes to disease progression in SIV-infected rhesus macaques 65

Abstract 66

Introduction 67

Materials and Methods 70

Results 76

Discussion 86

Figures 92

Chapter Four: CTLA-4 and PD-1-expressing CD4+ T cells are key contributors to viral persistence in ART-suppressed SIV-infected rhesus macaques 110

Abstract 111

Introduction 112

Materials and Methods 115

Results 123

Discussion 132

Figures 139

Chapter Five: Discussion 159

References 183

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