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).