Adjuvanting and delineating the mechanisms of induction of gut homing CD8 T cells elicited Open Access

Abstract

An efficacious HIV (Human immunodeficiency Virus) vaccine is crucial to curb
the global pandemic of the disease, AIDS. Gene-based (DNA) and viral-vector based
vaccines are two vaccine design strategies that are in advanced stages of development.
Here, we investigate the potential of co-stimulation through 4-1BB as an adjuvant for a
HIV-1 DNA vaccine in mice. We designed plasmid DNAs expressing either the
membrane bound or soluble form of 4-1BBL, and compared with the agonistic anti-4-
1BB Ab for their ability to adjuvant the Gag DNA vaccine. Both, anti-4-1BB agonistic
Ab as well as 4-1BBL DNA enhanced the Gag-specific cellular immune responses.
However, in complete contrast to the agonistic Ab that suppressed humoral immunity to
Gag, 4-1BBL DNA adjuvanted vaccines enhanced Gag-specific IgG responses.
Importantly, the expression of Gag and 4-1BBL from the same plasmid was critical for
the adjuvant activity. Collectively, our data suggest that for a HIV-1 vaccine, 4-1BBL
expressed by a DNA vaccine is a superior adjuvant than anti-4-1BB agonistic Ab.
An effective HIV vaccine must also be able to confer protective immunity at the
gut-associated mucosal tissue. Recent studies have shown that intramuscular
immunization with some live viral vectors can prime antigen-specific CD8 T cells with
gut homing potential. However, the mechanisms by which parenteral immunizations
elicit antigen-specific CD8 T cells in the gut are not understood. Here we show that an
adenovirus type 5 (Ad5) based HIV-1 vaccine primes a strong and durable antigen-
specific CD8 T cell response in the gut following intramuscular immunization in mice.
We also show that Ad5 rapidly induces expression of retinal dehydrogenase enzymes in
splenic conventional DC (cDC) and enhances their ability to prime antigen-specific CD8
T cells with gut homing specificity in vitro. This effect of Ad5 did not require signaling
through toll-like receptors, DNA-dependent activator of IRFs and several MAP kinases,
or replication capacity of the virus, but was dependant on NF-ï«B. These results provide
an innate mechanism through which Ad5 primes antigen-specific CD8 T cells with gut
homing potential and have implications for the development of novel mucosal adjuvants
for subunit vaccines administered via the intramuscular route.

Table of Contents

Table of Contents
Distribution Agreement
Approval Sheet
Dissertation Abstract Cover Page
Abstract
Dissertation Cover Page
Acknowledgements
Table of Contents
List of Figures

Chapter 1: Introduction

A. Pathogenesis of the Human immunodeficiency virus-1(HIV-1)
A.1. Basic Virology of HIV-1





1
A.2. Immunology of HIV-1 infection




3
B. HIV Vaccines
B.1. Correlates of immune protection




6
B.2. Challenges in designing a HIV vaccine



7
B.3. HIV Vaccine strategies





8
B.3.i. Strategies to adjuvant DNA vaccines


13

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Keyword	Mucosal Homing Adjuvant HIV vaccine DNA Vaccine
Committee Chair / Thesis Advisor	Amara, Rama Rao, Emory University
Committee Members	Speck, Sam, Emory University Robinson, Harriet, Emory University Mittler, Robert S, Emory University Hunter, Eric, Emory University

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