Gp120-induced conformational change in CD4 is important for HIV-mediated syncytium formation.

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

Gp120-induced conformational change in CD4 is important for HIV-mediated syncytium formation.

Int Conf AIDS. 1992 Jul 19-24;8(1):Mo14 (abstract no. MoA 0050). Unique Identifier : AIDSLINE ICA8/92400006
Manzoni C; Mous J; Pharma Research New Technologies, Hoffmann-La Roche Ltd, Basel,; Switzerland.

Abstract: OBJECTIVE: To study the mechanism of HIV-entry and identify novel ways of interfering with post-binding steps. RESULTS: During our mutational analysis of HIV-1 gp120--CD4 interaction, we identified a peculiar CD4 mutant, called V1*, which was characterised by a different folding pattern (no binding of Leu3a or gp120) and by the ability to enhance the spread of HIV infection by promoting cell fusion. MAb raised against mutant CD4 V1* inhibited this enhancing effect, whilst e.g. Leu3a could not block the V1*-induced syncytium formation. Moreover, V1* mAb displayed HIV neutralising activity, although it neither bound to native CD4 nor to gp120. This surprising result indicated that V1* mAb interfered with a step after binding of gp120 to its receptor CD4. Immunological binding studies indicated that after binding of gp120 to CD4, the receptor underwent a conformational change mimicking V1*. This became evident by the fact that V1*mAb, which recognizes V1* but not native V1, interacted with CD4 only when complexed with gp120. Initial studies also indicated that recombinant V1* interacts with a specific receptor on T-cell lines. This finding suggests that the binding of gp120-induced V1* like CD4 determinants to this factor X is important for the induction of membrane fusion, which would explain both the fusion-enhancing effect of recombinant V1* and the neutralizing activity of anti-CD4 V1* mAb. CONCLUSION: We identified a novel HIV neutralisation principle which is based on the interference with a specific step after the binding of gp120 to its receptor.

Keywords: Antibodies, Monoclonal/IMMUNOLOGY Antigens, CD4/*CHEMISTRY/GENETICS/IMMUNOLOGY/METABOLISM *Cell Fusion *Cytopathogenic Effect, Viral Human HIV Envelope Protein gp120/METABOLISM/*PHYSIOLOGY HIV-1/*PHYSIOLOGY Mutation Protein Binding Protein Conformation ABSTRACT
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M92C5341

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