Document 0191
 DOCN  M9440191
 TI    The phorbol ester phorbol myristate acetate inhibits human
       immunodeficiency virus type 1 envelope-mediated fusion by modulating an
       accessory component(s) in CD4-expressing cells.
 DT    9404
 AU    Golding H; Manischewitz J; Vujcic L; Blumenthal R; Dimitrov DS; Division
       of Virology, CBER, Food and Drug Administration,; Bethesda, Maryland
       20892.
 SO    J Virol. 1994 Mar;68(3):1962-9. Unique Identifier : AIDSLINE
       MED/94149892
 AB    The phorbol ester phorbol myristate acetate (PMA) strongly inhibits
       human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation;
       it has been suggested that this inhibitory effect is due to the
       transient downmodulation of the surface-associated CD4 receptors by PMA
       (I. H. Chowdhury, Y. Koyanagi, S. Kobayashi, Y. Hamamoto, H. Yoshiyama,
       T. Yoshida, and N. Yamamoto, Virology 176:126-132, 1990). Surprisingly,
       PMA treatment of cells expressing truncated (A2.01.CD4.401) and hybrid
       (A2.01.CD4.CD8) CD4 molecules, which are not downmodulated (P. Bedinger,
       A. Moriarty, R. C. von Borstel II, N. J. Donovan, K. S. Steimer, and D.
       R. Littman, Nature [London] 334:162-165, 1988), inhibited their fusion
       with CD4- (12E1) cells expressing vaccinia virus-encoded HIV-1 envelope
       glycoprotein (gp120-gp41) and with chronically HIV-1-infected H9 (MN,
       IIIB, or RF) cells. PMA pretreatment of T (12E1) and non-T (HeLa,
       U937.3, and Epstein-Barr virus-transformed B) cell lines expressing
       vaccinia virus-encoded CD4 also blocked fusion with 12E1 cells
       expressing vaccinia virus-encoded gp120-gp41. Interestingly,
       pretreatment of the gp120-gp41-expressing 12E1 cells with PMA did not
       alter their fusion with untreated CD4-expressing cells. Although the
       inhibitory effect of PMA was rapid and treatment for 1.5 h with 5 ng of
       PMA per ml was sufficient to reduce fusion by more than 50%, the
       recovery after treatment was slow and more than 40 h was needed before
       the cells regained half of their fusion potential. The inhibitory effect
       of PMA was blocked by staurosporine in a dose-dependent fashion,
       suggesting that it is mediated by protein kinase C. PMA treatment of
       A2.01.CD4.401 cells reduced the number of infected cells 6.7-fold, as
       estimated by a quantitative analysis of the HIV-1 MN infection kinetics,
       probably by affecting the stage of virus entry into cells. CD26 surface
       expression was not significantly changed by PMA treatment. We conclude
       that PMA inhibits the CD4-gp120-gp41-mediated fusion by modulating an
       accessory component(s), different from CD26, in the target
       CD4-expressing cells. These findings suggest a novel approach for
       identification of accessory molecules involved in fusion and may have
       implications for the development of antiviral agents.
 DE    Alkaloids/PHARMACOLOGY  Antigens, CD4/*PHYSIOLOGY  Antigens,
       Differentiation, T-Lymphocyte/PHYSIOLOGY  Cell Fusion/DRUG EFFECTS  Cell
       Line  Dose-Response Relationship, Drug  Drug Interactions  Giant
       Cells/PHYSIOLOGY  Human  HIV Envelope Protein gp120/PHYSIOLOGY  HIV
       Envelope Protein gp41/PHYSIOLOGY  HIV-1/*DRUG EFFECTS/GROWTH &
       DEVELOPMENT  Membrane Fusion/*DRUG EFFECTS  Models, Biological  Protein
       Kinase C/ANTAGONISTS & INHIB  Support, U.S. Gov't, P.H.S.
       Tetradecanoylphorbol Acetate/*PHARMACOLOGY  Virus Replication/DRUG
       EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).