A novel PDI DNA-based vaccination strategy to mimic Gag-specific responses found in HIV Elite controllers

Professor Chen, Zhiwei   (Principal Investigator (PI))

Dr Chen Leeye   (Co-Investigator)

Professor Lambotte Olivier   (Co-Investigator)

Dr Appay Victor   (Co-Investigator)

Professor Wei Qiang   (Co-Investigator)

Dr Chakrabarti Lisa A.   (Co-principal investigator)

48

2015-04-01

2550114

A novel PDI DNA-based vaccination strategy to mimic Gag-specific responses found in HIV Elite controllers

AIDS, dendritic cells, Elite Controllers, HIV, PDI-based Vaccine

Infection/Parasitology,Allergy/Immunology

A-HKU709/14

ANR / RGC Joint Research Scheme

2014

Completed

AIDS remains one of the most devastating infectious diseases, with over 35 million people infected worldwide. A recent HIV vaccine candidate has for the first time shown a moderate efficacy of 31Yo in phase III trial [1], which demonstrated the need for improved vaccine strategies against HIV. One of the obstacles remaining for candidate vaccine evaluation is that correlates of protection against HIV remain poorly defined. However, a series of studies have shed light on the antiviral immune response in HlV-infected patients who spontaneously control the virus in the absence of therapy. Our groups (teams FRI and FR2) have shown that these rare patients, called HIV Elite Controllers, develop T cell responses that are particularly efficient at sensing low amounts of virus [2, 3) and at eliminating infected cells [4]. This efficiency arises from the selection and expression of particular T cell receptors (TCRs) with a high avidity for epitopes located in the capsid of HIV, the Gag p24 protein Developing a vaccine that induces Gag responses similar to those seen in controllers represents a key objective, as such high-sensitivity responses are needed to contain limiting amounts of infecting HIV virions at a very early stage, before the virus has time to spread systemically. Our project will build on a novel vaccination platform that was shown to induce high frequency, high-sensitivity, and persistent Gag responses in mice [5]. The vaccination platform, developed by team HKl, relies on a DNA vector that encodes a soluble-PDI-Gag fusion protein. The soluble PDl moiety (sPDl) markedly enhances Gag immunogenicity, due to an efficient targeting of the immunogen to dendritic cells (DC) that express ligands of the PD1 receptor. The strategy chosen is based on in vivo electroporation of the sPDl-Gag DNA vaccine, because this technique induces the recruitment of DC to the site of vaccination. Electroporation represents one of the most promising avenue for DNA vaccine delivery, as it increases immunogen expression 10-100 fold as compared to simple DNA injection [6]. For this project, we will use the TERESA electroporation device developed by our industrial partner (team HK2), who is conducting a clinical phase IIb trials for DNA vaccination in China. The project will focus on a preclinical evaluation of the sPDl-Gag vaccine in three systems, including human cell cultures, a mouse model, and a non-human primate model. At each step, we will use the responses measured in HIV or SIV Elite Controllers as a benchmark for optimal vaccine responses. These experiments will provide preclinical data to support a future trial of the sPDl-Gag vaccine in humans, and will more generally further the development of DNA vaccination strategies against HIV.