by Soloff, Adam Christopher

Abstract (Summary)
A vaccine capable of preventing or therapeutically limiting human immunodeficiency virus (HIV) pathogenesis is urgently needed to contain the acquired immunodeficiency syndrome (AIDS) pandemic. Recombinant adenovirus (Ad)-based vectors are being explored as vaccine candidates due to their potent induction of cell-mediated immunity. To circumvent the limitations of vector-specific humoral immunity, novel Ad serotypes impervious to pre-existing immunity against conventional vectors have been developed. Utilizing the nonhuman primate model of HIV infection, we evaluated the immunogenicity of conventional Ad serotype 5- (Ad5) and novel serotype 35- (Ad35) based vaccinations against simian immunodeficiency virus (SIV) infection. In a preventative, proof-of-concept vaccination regimen, immunization against the SIV Gag protein proved highly efficacious, demonstrating robust boosting of Ad5-based vaccine-induced cellular immunity by Ad35-based vectors. Ad5/Ad35-based vaccination induced durable, high-frequency effector T cell responses that were later recalled upon heterologous SIV challenge. Vaccination resulted in modest reductions in SIV viremia, notable given the limited scope of immunization. We then tested the capacity of Ad5/Ad35-based vaccination targeting the SIV Gag, Env, and Nef proteins, with or without IL-15 augmentation, to promote cellular immunity during antiretroviral-treated chronic SIV infection with the goal of limiting rebound viremia following cessation of antiretroviral therapy (ART). Vaccination enhanced both systemic and mucosal antigen-specific cell-mediated immunity, increasing the breadth and strength over innate response to infection. Ad-induced immunity consisted of CD4+ and CD8+ T lymphocyte TH1 cytokine production of a predominantly monofunctional nature. Furthermore, vaccination enhanced both central and effector memory CD4+ and CD8+ T cell populations without augmenting niave T cell responses. Although Ad-based immunotherapy transiently restored the systemic central memory CD4+ T cell compartment, vaccination failed to salvage effector memory or mucosal CD4+ T cells. Therapeutic intervention was associated with transient containment of rebound viremia upon ART cessation which vaccination failed to augment. An effective vaccination against HIV represents the most efficient method to end the AIDS pandemic, and is of considerable public health significance. The findings presented herein provide evidence to support the continued evaluation of Ad-based vectors in novel treatment strategies against HIV infection, representing an incremental advancement in the field of HIV vaccine development.
Bibliographical Information:

Advisor:Joanne Flynn; Simon Barratt-Boyes; Kelly Stefano Cole; Charles Rinaldo; Andrea Gambotto

School:University of Pittsburgh

School Location:USA - Pennsylvania

Source Type:Master's Thesis

Keywords:infectious diseases and microbiology


Date of Publication:01/29/2009

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