Objective
- To elucidate the molecular mechanisms underlying antibody mediated neutralisation and enhancement of lentivirus entry
- to determine similarities in structure-function relationships in antibody mediated neutralisation and enhancement of HIV-1, HIV-2 and FIV entry
- to determine the role of antibody mediated neutralisation and enhancement of lentivirus infection in pathogenesis and vaccine development
SUMMARY Virus neutralizing antibodies are generally considered to play a major role in the pathogenesis and immune mediated protection of lentivirus infections. Recently others and we have shown that -both in vifro and invivo- these antibodies may mediate enhancement rather than protection against virus infectivity in primate and feline lentivirus systems. The outcome of the virus-antibody interaction proved to be determined by the molecular structure of the viral envelope glycoproteins and should therefore be directly influenced by their genetic variability. Antibody specificity proved to be of secondary importance only. Especially in the light of ongoing clinical trials with candidate HIV and FIV vaccines this issue has raised major concern, since vaccination with currently considered vaccines could induce antibodies that paradoxically, may rather increase susceptibility to infection and accelerate disease progression. Furthermore it raises concerns about certain vaccine development strategies. The project aims to elucidate mechanisms involved in antibody mediated virus neutralization and enhancement at the molecular level, with special emphasis on the structural features which determine the efficiency of lentivirus entry.
To this end the following objectives will be pursued:
In vitro identification of primate and feline lentivirus envelope regions, directly involved in antibody mediated neutralization and enhancement of virus infectivity. Mutational and chimeric protein analyses will be carried out with special emphasis on similarities in possible structure function relationships, between the respective systems.
In vitro structure-function analyses of interactions between antibodies and the soluble form of the receptor on the one hand, and the primate and feline lentivirus envelopes on the other hand, using molecular genetic, physical and chemical methods.
The thus generated in vitro data will form the basis for subsequent in vivolaboratory animal studies:
In vivo analysis of the role of antibody mediated neutralization and enhancement of HIV-1 and HIV-2 infectivity, in the pathogenesis of these infections in a human to mouse chimeric animal model.
In vivo analysis of the role of neutralization and enhancement mediated by antibodies, which have either been generated by infection or by vaccination, in the pathogeneses of macaque HIV-2 and cat-FlV infections. The research proposed is of major importance for our understanding of the immune-pathogenesis of AIDS in man and animals and the involvement of different antibody populations in this process. Furthermore, it will directly contribute to a more rational and safe approach for AIDS vaccine development.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences microbiology virology
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences health sciences infectious diseases RNA viruses HIV
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs vaccines
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Coordinator
3015 GE ROTTERDAM
Netherlands
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