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Document 3333
DOCN M94A3333
TI Mechanisms of HIV-1 envelope glycoprotein-mediated membrane fusion.
DT 9412
AU Dimitrov DS; Golding H; Broder CC; Blumenthal R; National Cancer
Institute, NIH, Bethesda, MD 20892.
SO Int Conf AIDS. 1994 Aug 7-12;10(1):10 (abstract no. 015A). Unique
Identifier : AIDSLINE ICA10/94369242
AB OBJECTIVE: To delineate factors affecting the kinetics of membrane
fusion mediated by the HIV-1 envelope glycoprotein (gp120-gp41 complex).
METHODS: Kinetics of cell-cell and virus-cell membrane fusion was
measured by assays based on redistribution of fluorescent dyes,
photoinactivation, syncytia formation and infection kinetics. A
theoretical model, based on kinetic considerations, was develop to
analyze the experimental data. RESULTS: We found that i) cell-cell
fusion required much longer (10-fold) delay than virus-cell fusion, ii)
the delay decreased with an increase in the cell surface-associated
gp120-gp41 but was not significantly affected by the CD4 surface
concentration, iii) a hybrid CD4.CD8 molecule, where the two proximal
membrane domains, the transmembrane and cytoplasmic domains were
replaced with domains from human CD8, supported fusion with 5-fold
longer delay than wild type CD4, iv) some anti-CD4 antibodies, which
bind to epitopes outside the gp120 binding site, slowed down strongly
the kinetics of cell fusion, but did not affect significantly the extent
of fusion after long times (24 hours) and v) syncytia formation was
slower than cell-cell membrane fusion and strongly dependent on the
gp120-gp41 surface concentration. The theoretical analysis of these and
other data indicated that the delay in fusion may be due to kinetic and
energy barriers related to binding kinetics of the fusing membranes and
conformational changes in the CD4-gp120-gp41 complex. CONCLUSIONS:
Quantitative data and theoretical analysis of membrane fusion kinetics
suggest that fusion occurs through a number of steps, including membrane
approach, binding, conformational changes in the CD4-gp120-gp41 complex
and formation of fusion pores. These steps may also determine whether
membrane fusion will proceed to syncytia formation and could differ for
syncytium-inducing and non-syncytium-inducing virus isolates.
DE Antigenic Determinants/IMMUNOLOGY Antigens, CD4/IMMUNOLOGY Antigens,
CD8/IMMUNOLOGY Human HIV Envelope Protein gp120/*PHARMACOLOGY HIV
Envelope Protein gp41/*PHARMACOLOGY Membrane Fusion/*DRUG EFFECTS
Viral Matrix Proteins/METABOLISM MEETING ABSTRACT
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).