The latent viral reservoir is composed of a small subset of infected CD4+ T cells that persist during antiretroviral therapy (ART) and constitute the major barrier to HIV-1 cure. Strategies to reduce or eliminate this reservoir would be highly beneficial to the 1.7 million children living with HIV-1. Here, we used a non-human primate (NHP) model of postnatal oral SIVmac251 transmission and ART suppression to investigate potential cure interventions in a preclinical pediatric model of HIV-1 infection.
First, we evaluated safety and immunogenicity of the toll-like receptor (TLR)-7 agonist, GS-986, in 2 SIV-infected, ART-treated infant rhesus macaques (RMs). We found that oral administration of GS-986 at both tested concentrations was tolerable and resulted in a dose-dependent pharmacodynamic response detectable through increased concentrations of plasma cytokines and chemokines, such as IFN-𝛾 and increased circulating nonclassical monocytes (CD14+CD16+) and circulating macrophages (CD14+CD169+) at 24 hours post-administration.
We next combined GS-986 with an Ad48-prime, MVA-boost therapeutic vaccine in 8 SIV-infected, ART-treated infant RMs. Immunized infants had augmented anti-SIV cellular and humoral immunity. Repeated oral GS-986 induced the expected pharmacodynamic response with activation of monocytes and T cells in the periphery 24-hours post-dose. Despite the vaccine-induced immune responses, vaccination did not result in reductions to the viral reservoir through cell-associated SIV DNA or rebound kinetics following the removal of ART.
Finally, we examined the effect of a newly identified latency reversing agent (LRA), the mimetic of second mitochondrial activator of caspases (SMACm) AZD5582, in 8 SIV-infected, ART-suppressed infant RMs. Latency reversal, measured by on-ART viremia, was observed in 63% of infants. Immunogenicity of AZD5582 was demonstrated through T cell activation and increased transcription of ncNF-kB genes, such as BIRC3. Quantification of plasma AZD5582 revealed a lower Cmax in infants compared to adult RMs which may, in part, explain the dampened viremia.
Taken together, these findings hold promise for pediatric HIV-1 cure strategies and inform future pediatric clinical trials. Additionally, these studies highlight the importance of studying HIV-1 cure in a pediatric setting as unique features of the pediatric reservoir and/or the developing immune system may influence the efficacy of HIV-1 cure interventions.
Table of Contents
Table of Contents
Chapter One: Introduction 1
Discovery and Origins of HIV-1/AIDS 1
Virology and HIV-1 Life Cycle 2
Transmission and Pathogenesis of HIV-1 5
The Immune Response to HIV-1 8
Non-human Primate Models 10
Antiretroviral Therapy 12
The Viral Reservoir 14
Strategies for HIV-1 Cure 16
Pediatric HIV-1 21
Chapter 1 Summary 29
Chapter 1 Figures 31
Chapter Two: Oral TLR7 Agonist Administration Induces an Immunostimulatory Response in SIV-Infected ART-Suppressed Infant Rhesus Macaques 32
Author Summary 34
Materials and Methods 45
Chapter Two Figures 50
Chapter Three: Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation 57
Author summary 60
Materials and Methods 80
Chapter 3 Figures 89
Chapter Four: Altered response patterns following non-canonical NF-B activation in SIV-infected, ART-suppressed rhesus macaque infants 112
Author Summary 114
Materials and Methods 131
Chapter 4 Figures 140
Chapter Five: Discussion 153
List of Abbreviations 165
About this Dissertation
|Subfield / Discipline
|Committee Chair / Thesis Advisor
|Investigation of Immune Interventions in SIV-Infected, ART-Treated Infant Rhesus Macaques ()
|2021-11-08 12:00:57 -0500