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Imaging of HIV-1 Envelope-induced Virological Synapse and Signaling on Synthetic Lipid Bilayers
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Imaging of HIV-1 Envelope-induced Virological Synapse and Signaling on Synthetic Lipid Bilayers

Published on: March 8, 2012

The phorbol ester phorbol myristate acetate inhibits human immunodeficiency virus type 1 envelope-mediated fusion by

H Golding1, J Manischewitz, L Vujcic

  • 1Division of Virology, CBER, Food and Drug Administration, Bethesda, Maryland 20892.

Journal of Virology
|March 1, 1994
PubMed

Insights

Phorbol myristate acetate (PMA) inhibits HIV-1 fusion by affecting accessory molecules, not CD4 receptors. This discovery offers a new strategy for developing antiviral therapies against HIV-1 infection.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Phorbol ester phorbol myristate acetate (PMA) is known to inhibit human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation.
  • This inhibition was previously attributed to PMA's transient downmodulation of surface-associated CD4 receptors.

Purpose of the Study:

  • To investigate the mechanism by which PMA inhibits HIV-1-induced fusion.
  • To determine if PMA's inhibitory effect is dependent on CD4 receptor downmodulation.
  • To identify potential accessory molecules involved in PMA-mediated inhibition of HIV-1 fusion.

Main Methods:

  • Treatment of cells expressing various CD4 molecules (truncated, hybrid, and vaccinia virus-encoded CD4) with PMA.
  • Assessing cell fusion with cells expressing HIV-1 envelope glycoproteins (gp120-gp41) or chronically HIV-1-infected cells.
  • Investigating the kinetics of PMA's inhibitory effect and recovery.
  • Testing the effect of staurosporine on PMA-induced inhibition.
  • Quantifying HIV-1 infection kinetics following PMA treatment.

Main Results:

  • PMA inhibited fusion even when CD4 molecules were not downmodulated.
  • PMA pretreatment of CD4-expressing cells blocked fusion with gp120-gp41 expressing cells, but not vice versa.
  • The inhibitory effect of PMA was rapid, but recovery was slow (over 40 hours).
  • Staurosporine blocked PMA's inhibitory effect, suggesting protein kinase C involvement.
  • PMA treatment reduced HIV-1 infection by 6.7-fold, likely by affecting virus entry.
  • CD26 surface expression remained unchanged by PMA treatment.

Conclusions:

  • PMA inhibits CD4-gp120-gp41-mediated fusion by modulating accessory components in CD4-expressing cells, independent of CD4 receptor downmodulation.
  • These findings suggest a novel approach for identifying accessory molecules crucial for viral fusion.
  • The study has implications for developing new antiviral agents targeting HIV-1 entry.

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