Secreted phospholipases A(2), a new class of HIV inhibitors that block virus entry into host cells.
Mammalian and venom secreted phospholipases A(2) (sPLA(2)s) have been associated with a variety of biological effects. Here we show that several sPLA(2)s protect human primary blood leukocytes from the replication of various macrophage and T cell-tropic HIV-1 strains. Inhibition by sPLA(2)s results neither from a virucidal effect nor from a cytotoxic effect on host cells, but it involves a more specific mechanism. sPLA(2)s have no effect on virus binding to cells nor on syncytia formation, but they prevent the intracellular release of the viral capsid protein, suggesting that sPLA(2)s block viral entry into cells before virion uncoating and independently of the coreceptor usage. Various inhibitors and catalytic products of sPLA(2) have no effect on HIV-1 infection, suggesting that sPLA(2) catalytic activity is not involved in the antiviral effect. Instead, the antiviral activity appears to involve a specific interaction of sPLA(2)s to host cells. Indeed, of 11 sPLA(2)s from venom and mammalian tissues assayed, 4 venom sPLA(2)s were found to be very potent HIV-1 inhibitors (ID(50) < 1 nM) and also to bind specifically to host cells with high affinities (K(0.5) < 1 nM). Although mammalian pancreatic group IB and inflammatory-type group IIA sPLA(2)s were inactive against HIV-1 replication, our results could be of physiological interest, as novel sPLA(2)s are being characterized in humans.
Fenard
D
D
Laboratoire de Virologie, Faculté de Médecine, 06107 Nice cédex 2, France Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France.
Lambeau
G
G
Valentin
E
E
Lefebvre
J C
JC
Lazdunski
M
M
Doglio
A
A
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001514:Bee Venoms / Q000201:enzymology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D015726:Giant Cells / Q000187:drug effects; D054501:Group II Phospholipases A2; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000821:virology; D008322:Mammals / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects; D010741:Phospholipases A / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011533:Proviruses / Q000187:drug effects / Q000235:genetics; D019713:Receptors, CCR5 / Q000378:metabolism; D012910:Snake Venoms / Q000201:enzymology; D014688:Venoms / Q000201:enzymology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D001514:Bee Venoms; D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D012910:Snake Venoms; D014688:Venoms; D010741:Phospholipases A; D054501:Group II Phospholipases A2