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Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans
L Wagner1, O O Yang, E A Garcia-Zepeda
1Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Insights
Human immunodeficiency virus (HIV)-1-specific CD8+ cytotoxic T lymphocytes (CTL) release both cytolytic and chemokine mediators together. These CTLs inhibit viral replication through cell lysis and by preventing viral entry into new cells.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- CD8+ lymphocytes play a crucial role in host defense against HIV-1.
- HIV-1 replication is inhibited by CD8+ lymphocytes via cytolytic and non-cytolytic pathways.
Purpose of the Study:
- To investigate the localization and co-secretion of cytolytic and chemokine mediators by HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL).
- To understand the functional significance of these mediators in controlling HIV-1 infection.
Main Methods:
- Used granzyme A as a marker for cytolytic granule proteins.
- Utilized macrophage inflammatory protein (MIP)-1alpha and RANTES as markers for HIV-1 inhibitory chemokines.
- Analyzed the secretion of these mediators following antigen-specific activation of CTLs.
Main Results:
- Both cytolytic (granzyme A) and non-cytolytic (MIP-1alpha, RANTES) mediators are localized within the cytolytic granules of HIV-1-specific CTLs.
- These mediators are co-secreted upon antigen-specific activation, contributing to both cell lysis and free virus inhibition.
- RANTES, MIP-1alpha, and MIP-1beta are secreted as a complex with sulphated proteoglycans, with heparan sulphate enhancing RANTES's inhibition of HIV-1 infection in monocytes.
Conclusions:
- HIV-1-specific CTLs employ a dual-action mechanism involving co-localized cytolytic and chemokine mediators for effective viral control.
- The co-secretion of these mediators enhances the inhibition of both infected cells and free virus.
- Proteoglycan association with chemokines, particularly heparan sulphate with RANTES, is functionally significant for inhibiting monocyte infection.
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 pathways. The cytolytic pathway involves calcium-dependent exocytosis of perforin and granzyme proteases, as well as Fas-mediated programmed cell death, whereas the noncytolytic pathway involves the release of chemokines that prevent viral entry. Using granzyme A as a marker of cytolytic granule proteins, and macrophage inflammatory protein (MIP)-1alpha 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-1alpha and MIP-1beta 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.