Novel Vaccines and Therapeutic Approaches Against HIV-1 公开
Chea, Lynette (Spring 2019)
Abstract
Currently, approximately 37 million people are infected with Human Immunodeficiency Virus-1 (HIV) world-wide and there is a great need for developing both preventative and functional cure approaches to control the epidemic. Advancements toward a preventive vaccine and functional cure for HIV have made significant progress in the past decade. A successful vaccine aims to achieve antibody and T cell responses of high magnitude and durability to prevent infection. Thus, the development of vaccine delivery vectors to generate potent immune responses is critical. Modified vaccinia Ankara (MVA) has been used as a promising viral vaccine vector for inducing vaccine-specific humoral and cellular responses against multiple infectious diseases including HIV. A primary goal of this dissertation was to further enhance the immunogenicity of MVA by targeting the apoptotic pathway induced after MVA infection of cells. We provide evidence that delaying apoptosis during MVA vaccination improves antigen-specific humoral responses. We generated an MVA expressing an anti-apoptotic gene B13R, MVA-B13R, and showed that MVA-B13R infection markedly delays apoptosis of infected cells. We further demonstrate that MVA-B13R expressing Simian Immunodeficiency Virus (SIV) and HIV antigens develop greater vaccine-induced humoral responses with enhanced durability. Interestingly, MVA-B13R immunization resulted in a delayed interferon response. These findings report a novel MVA that can be used as a vaccine vector for enhancing humoral immunity against multiple infectious diseases.
HIV cure research aims to allow individuals to control viremia in the absence of anti-retroviral therapy (ART). Dysfunctional anti-viral immunity and persistence of the latent HIV reservoir are the main barriers to HIV cure. This dissertation additionally aimed to investigate the ability of PD-1 checkpoint blockade therapy combined with ART to restore and improve anti-viral immunity and reduce the HIV viral reservoir. Our findings demonstrate that this regimen enhanced anti-viral CD8+ T cell functionality and destabilized the viral reservoir leading to improved control of viral rebound after ART interruption. This study provides evidence that PD-1 blockade co-administered with ART can effectively enhance immune functionality during chronic SIV infection and establishes the foundation for identifying optimal HIV cure therapies.
Table of Contents
TABLE OF CONTENTS
CHAPTER I Introduction … 1
CHAPTER II Novel MVA Vector Expressing Anti-apoptotic Gene B13R Delays Apoptosis and Enhances Humoral Responses … 49
CHAPTER III Combination Anti-PD-1 and Anti-retroviral Therapy Provides Therapeutic Benefit Against SIV … 85
CHAPTER IV Discussion & Future Directions …160
CHAPTER V Bibliography …177
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