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Generation of broadly cross neutralising Antibodies for innovative active-passive HIV Vaccination Strategies based on modified Ig-gene transgenic mice


For improved protection from HIV infection during birth or through accidental exposure to HIV, antibodies with broad neutralizing activity would be a valuable addition to antiretroviral treatment and to vaccines. So far in the field of HIV applied resear ch only few antibodies with broad cross clade neutralizing properties are available (b12, 2G12, 2F5 and 4E10). They recognize either epitopes presented only transiently during infection of cells, or epitopes not recognizable 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 (ie 2G12) to generate mice with germ line modified immunoglobulin genes which introduce extended mobility into th e 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 i mmunization to favour receptor mediated transitory stages of the viral envelope. Previous experience and reagents from earlier EU funded programmes (virosome incorporating HIV proteins PN 012183) and new microbicide-vaccine combinations against HIV (subm. call LSH-2004-2.3.0-1 with R. Shattock) 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 vacc ines in CD4 transgenic mice to generate monoclonal antibodies with novel broadly neutralizing properties. This proof of principle can directly give valuable reagents. It can also be further developed into humanized antibodies. The novel antibodies develo ped out of this programme will be valuable additions to the immunogens developed by the EUROVAC group in the context of FP5. The C-clade chosen is of major importance in the worldwide HIV epidemic.

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Franz-Josef-Strauss-Allee 11

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