β-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans

CD8(+) lymphocytes are believed to be important in host defence against the human immunodeficiency virus (HIV)-1, inhibiting HIV-1 replication through both cytolytic and non-cytolytic pathways(1-13). The cytolytic pathway involves calcium-dependent exocytosis of perforin and granzyme proteases, as well as Fas-mediated programmed cell death(4), whereas the noncytolytic pathway involves the release of chemokines that prevent viral entry(5). Using-granzyme A as a marker of cytolytic granule proteins, and macrophage inflammatory protein (MIP)-1 alpha and RANTES as markers of HIV-1 inhibitory chemokines, we show that these two very different mediators of viral inhibition are both localized in the cytolytic granules of HIV-1-specific CD8(+) cytotoxic T lymphocytes (CTL). Following antigen-specific activation, these mediators are secreted together facilitating both lysis of virion-producing cells and the inhibition of free virus. In addition, RANTES, MIP-1 alpha and MIP-1 beta are secreted by CTL as a macromolecular complex containing sulphated proteoglycans. This association appears to have a functional significance, because heparan sulphate facilitates RANTES inhibition of HIV-1 infection of monocytes.