Investigating the contribution of CD4+ T cell subsets to SIV disease progression and persistence Öffentlichkeit
McGary, Colleen Shannon (2016)
Abstract
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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