Assessing the Immunogenicity of GTU-based HIV-1 Multigene
DNA Vaccines in Murine Models
Acta Universitatis Tamperensis No. 1621
By Maria Malm
Tampere University Press
Distributed by Coronet Books
$85.00 Paper original
HIV-1 vaccine development has proven an extremely challenging task, largely related to the highly variable nature of the virus which generates constantly new variants able to escape the immune system surveillance and lack of correlates of protection. DNA vaccines have the potential to encode multiple viral antigens, thereby eliciting immune responses that could lead to improved containment of the HIV-1 virus in a relatively safe way. Furthermore, the endogenous synthesis of the plasmid encoded antigen mimics the viral replication and enables the antigen presentation in a natural way for immune system cells.
The first aim of this study was to evaluate the immunogenicity of the HIV-1 multigene DNA plasmid vaccine, encoding for Rev, Nef, Tat, p17, p24 and selected T cell epitopes of HIV-1 pol and env in mice. GTU® vector encoding the multigene is an advanced expression vector resulting in higher expression level and longer maintenance of the plasmid in dividing cells compared to conventional DNA plasmids. In the first part of the work, we demonstrated that GTU®-MultiHIV DNA induces cellular and humoral immune responses in mice directed to all components of the HIV-1 multigene. Delivery route and DNA dose used were shown to be major determinants for the efficiency of the immunization. Biolistic gene gun delivery induced strong immune responses with very low DNA doses, whereas intradermal and intramuscular administrations were dependent on high DNA doses. The induced cellular immune responses as measured by IFN-gamma secretion were shown to correlate with cytotoxic T cell activity in vitro and in vivo.
To evaluate the protective efficacy of the HIV-1 DNA vaccine induced immune responses, we developed a novel tumor challenge model. We showed that HIV-1 specific cellular immune responses were able to significantly delay the growth of the HIV-1 antigen expressing tumor, thereby demonstrating the cytotoxic activity of the induced T lymphocytes, which is an important characteristic of HIV-1 vaccine. Furthermore, the HIV-1 specific T cells activated by immunization were shown to efficiently clear the HIV-1/MuLV infected cells used for the challenge in another experimental challenge model. Indication of cross-clade protection was demonstrated by evaluating the protection induced by immunization with a multiclade specific plasmid cocktail, containing antigens derived from HIV-1 strains A–C and F-H and subsequently using different HIV-1 subtypes for the challenge. Finally, we briefly addressed the significant role of dendritic cells in eliciting immune responses by GTU®-MultiHIV DNA immunization.
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