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HIVAB

HIV/AIDS

Generation of Broadly Cross Neutralising Antibodies for Innovative Active-passive HIV Vaccination Strategies Based on Modified Ig-gene Transgenic Mice
Framework programme:
6
Call:
3
Project number:
LSHP-CT-2005-019052
EC contribution:
€ 950 000
Duration:
24 months
Type:
STREP
Starting date:
1 December 2005

Keywords: HIV; Vaccine; Neutralising Antibodies; transgenic mice

Summary:

For improved protection from HIV infection during birth or through accidental exposure to HIV, antibodies that have a broad neutralising activity would be a valuable addition to antiretroviral treatment and to vaccines. So far, there are only a few antibodies with broad cross-clade neutralising properties available in the field of HIV applied research – b12, 2G12, 2F5 and 4E10. They recognise either epitopes presented only transiently during infection of cells, or epitopes not recognisable by unmodified immunoglobulins (2G12). Two experimental strategies are used in separate and in combination. One uses the lead given by extremely rare mutant antibody genes (i.e. 2G12) to generate mice with germ line modified immunoglobulin genes, which introduce extended mobility into the immunoglobulin protein backbone. Immunisation of these mice will allow recognition of novel expanded epitopes including glycane clusters and the development of monoclonal antibody. The other line of experiments employs HIV receptor-transgenic mice for immunisation to favour receptor mediated transitory stages of the viral envelope.

Previous experience and reagents from earlier EU-funded programmes (virosome incorporating HIV proteins) and new microbicide-vaccine combinations against HIV to present native oligomeric HIV envelope of clinically relevant HIV isolates will be used in addition to liposome-presented recombinant C-clade gp 140 oligomers and gp160 encoding highly effective DNA plasmid vaccines in CD4 transgenic mice to generate monoclonal antibodies with novel broadly neutralising properties. This proof of principle can directly give valuable reagents. It can also be further developed into humanised antibodies. If successful, a fully human immunoglobulin-based strategy will be chosen as the next step. The novel antibodies developed out of this programme will be valuable additions to the immunogens developed by the EUROVAC group in the context of the Fifth Framework Programme. The C-clade chosen is of major importance in the worldwide HIV epidemic.

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