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

Abstract

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 pathways1,2,3. The cytolytic pathway involves calcium-dependent exocytosis of perforin and granzyme proteases, as well as Fas-mediated programmed cell death4, whereas the noncytolytic pathway involves the release of chemokines that prevent viral entry5. Using granzyme A as a marker of cytolytic granule proteins, and macrophage inflammatory protein (MIP)-1α 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-1α and MIP-1β 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.

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Figure 1: Quantification of chemokine mRNA, protein secretion and sulphated proteoglycan/glycosaminoglycan release from quiescent and activated CTL clones.
Figure 2: Size-exclusion chromatography of activated CTL supernatant.
Figure 3: Two-colour immunofluorescence confocal microscopy of an HIV-1-specific CTL clone in the absence of target cells (top row) and in the presence of HIV-1 peptide-loaded MHC compatible target cells (middle and bottom rows).
Figure 4: Inhibition of HIV-1 replication by RANTES in the presence or absence of heparan sulphate.

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Acknowledgements

We thank R. Stevens and M. Norcross for helpful discussions.

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Correspondence to Andrew D. Luster.

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Wagner, L., Yang, O., Garcia-Zepeda, E. et al. β-Chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature 391, 908–911 (1998). https://doi.org/10.1038/36129

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