BPRC Research | Research Programmes Human Health | Pox-Gene STREP

On this web page some of the key features are described of the Pox-Gene project, which is funded by the European Committee, and aims to develop a fundamentally new approach in the treatment of HIV infected patients.

Contract details:

Contract number: LSHB-CT-2005-018680

Project Acrony: Pox-Gene

Project full title: A combined pox-virus/lentiviral vector system to treat HIV infection. Immunization and direct in vivo gene transfer in T lymphocytes.

Priority/Priority component:

  • Life sciences, genomics and biotechnology for health (LifeSciHealth)
  • Confronting the major communicable diseases linked to poverty
  • Research in poverty-related diseases by SMEs - STREP

Total cost: €1.528.492
EC contribution: € 1.180.000
Duration: in months 36
Type: STREP
Starting date: 2005

Project main goals:

Worldwide, over 40 million people are infected with HIV and AIDS is a major cause of mortality, particularly in developing countries. Currently, the only effective treatment available is highly active anti-retroviral therapy (HAART). Despite its success, it is clear that HAART cannot eradicate the virus and that sustained treatment is required. However, lifetime treatment is not always practicable, particularly in developing countries. Therefore, additional therapies are urgently required. Our project’s goal is to combine therapeutic vaccination with direct in vivo gene transfer using a genetically modified vaccinia vector. This Pox-Gene strategy should provide effective disease intervention, which can then be used in developed as well as developing countries.

Key issues:

HIV-1 infection in humans severely perturbs T helper responses, leading to immune deficiency, the onset of opportunistic infections and acquired immunodeficiency syndrome (AIDS). While the advent of highly active anti-retroviral therapy (HAART) has greatly improved the immune status of HIV-1 infected patients by increasing their CD4 T cell counts and restoring specific responses to opportunistic infections, several problems still remain: 1) despite effective inhibition of virus production, CD4 T cell and dendritic cell numbers do not reach their normal pre-infection values; 2) immune responses directed against HIV-1 remain largely ineffective in controlling virus load; 3) serious side effects and long term toxicity as well as emergence of resistant viruses limit the long term effectiveness of HAART; and 4) the expense of these drugs, the constant need to monitor for the emergence of drug resistance, the required compliance to a very strict drug regime, and the vast population affected, make HAART unsuitable and unaffordable for developing countries.

Photo Courtesy of Neal R. Chamberlain
Studies in animal models and humans undergoing different types of chronic viral infections, including CMV, EBV etc. have shown that infection can be effectively controlled by specific memory CD4 and CD8 T cell subpopulations, which are impaired in patients chronically infected with HIV-1. In contrast, these responses are partially maintained in long term non progressors (LTNP) who better control virus replication in the absence of HAART. In this project, we propose to develop a treatment that will reinforce the patient’s immune response to HIV and render their T cells resistant to infection. This goal shall be achieved by a combined immunization-gene therapy protocol, leading to in vivo transduction of anti-HIV specific T cells with genes that project them against HIV infection.

Technical approach:

In this project, we shall exploit this knowledge and employ state of the art bioengineering to create a pox-virus vector that encodes, in addition to specific HIV-1 proteins, a fully functional lentiviral vector genome delivering heterologous genes with HIV inhibitory capacity. Cells infected with modified vaccinia virus ankara (MVA) will simultaneously be converted into packaging cells capable of releasing transducing particles and cells expressing HIV-1 proteins for the stimulation of antigen specific cells. Consequently, the Pox-Gene vector will serve a dual role as a therapeutic vaccine and as in vivo gene therapy. The transducing particles released in vivo will protect naïve, memory and activated T cells (including HIV antigen-specific T cells) from HIV infection. During the course of this project we shall demonstrate the Pox-Gene efficiency for transduction of T cells in vitro and in vivo using marker genes. Finally, after proof of concept has been achieved in mice, we will perform a small pilot study in SHIV infected macaques.

Expected achievements:
It is our strategic objective to develop an effective new intervention for one of the major communicable diseases, i.e. HIV infection of humans. The following exploitable therapeutic products are expected to emerge from this project:
1)    Pox-Gene vectors effective for antigen specific stimulation and transduction of T cells
2)    Gene constructs that are able to protect cells against infection with HIV
Over the course of this project these therapeutic products will be developed and tested in appropriate tissue culture systems and animal models, to evaluate their transduction efficiency, HIV infection inhibitory capacity, biodistribution and safety.

List of participants:

Gerrit Koopman, PhD, co-ordinator
Biomedical Primate Research Centre, Dept. of Virology, Lange Kleiweg 157, 2288 GJ Rijswijk, The Netherlands.
Web-site of organisation: www.bprc.nl

Dorothee von Laer, MD, Georg-Speyer-Haus, Applied Virology and Gene Therapy, Paul Ehrlich Strasse 42-4, 60596 Frankfurt, Germany.
Web-site of organisation: www.georg-speyer-haus.de

Gerd Sutter, DVM, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany. Tel. +49-(0)6103-772140; Fax +49-(0)6103-771273, Mail: sutge@pei.de. 
Web-site of organisation: www.pei.de

Balbino Alarcón, PhD
CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS (CSIC), Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Cantoblanco, ES-28049 Madrid, Spain.
Web-site of organisation: www.cbm.uam.es

Giuseppina Li Pira, PhD, Advanced Biotechnology Center, Largo Benzi 10, 16147 Genoa, Italy.
Web-site of organisation: www.biotecnologie.it

Karen Willard-Gallo, PhD, Université Libre de Bruxelles, Institut Bordet, Experimental Hematology, 121 Blvd de Waterloo, 1000 Bruxelles, Belgium.
Web-site of organisation: www.ulb.ac.be/rech/inventaire/unites/ULB612.html