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 assoc iated 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 viru s binding to cells nor on syncytia formation, but they prevent the intracel lular release of the viral capsid protein, suggesting that sPLA(2)s block v iral entry into cells before virion uncoating and independently of the core ceptor usage. Various inhibitors and catalytic products of sPLA(2)s have no effect on HIV-1 infection, suggesting that sPLA(2) catalytic activity is n ot involved in the antiviral effect. Instead, the antiviral activity appear s to involve a specific interaction of sPLA(2)s to host cells. Indeed, of 1 1 sPLA(2)s from venom and mammalian tissues assayed, 4 venom sPLA(2)s were found to be very potent HIV-1 inhibitors (ID50 < 1 nM) and also to bind spe cifically to host cells with high affinities (K-0.5 < 1 nM). Although mamma lian pancreatic group IB and inflammatory-type group IIA sPLA(2)s were inac tive against HIV-1 replication, our results could be of physiological inter est, as novel sPLA(2)s are being characterized in humans.