Neutralizing gp120-specific antibodies kill T cell line-adapted HIV-1 in three different ways: Group 1 MAbs inhibit attachment of virions to the target cell (1 of 7 MAbs tested), Group 2 MAbs inhibit fusion of the virion to the target cell (3 of 7 Mabs tested), and Group 3 Mabs are unique in indirectly inhibiting a post-fusion event (3 of 7 Mabs tested). The investigators argue here that Group 1 and 2 MAbs that inhibit attachment or fusion entry are likely to be most affected by variations in the properties of primary or secondary receptors of target cells, whereas Group 3 MAbs that inhibit a post-fusion step are less likely to be so affected, and are therefore the best choice for passive immunotherapy. Specifically this proposal will determine (a) if Group 3 Mabs also inhibit primary strains of HIV-1 by inhibition of a post-fusion step; (b) what function of the post-fusion virion-core particle of lab strains is inhibited and (c) the mechanism by which Group 3 MAbs bound to the gp120 on the exterior of the virion affect the functioning of the core particle on the other side of the viral membrane. The proposal will focus on the CD4-binding site-specific Fab of the human IgGb12, but will also investigate the V3 loop-specific IgG MAb ICR41.1i, as the different locations of of their epitopes suggest that more than one transmembrane transduction signal and more than one post-fusion function of the viral core may be involved.
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