Antigen-specific release of beta-chemokines by anti-HIV-1 cytotoxic T lymphocytes.
A major advance in understanding human immunodeficiency virus (HIV) biology was the discovery that the beta-chemokines MIP-1 alpha (macrophage inflammatory protein-1 alpha), MIP-1 beta (macrophage inflammatory protein-1 beta) and RANTES (regulated on activation, normal T-cell expressed and secreted) inhibit entry of HIV-1 into CD4+ cells by blocking the critical interaction between the CCR5 coreceptor and the V3 domain of the viral envelope glycoprotein gp120 [1,2]. CD8+ lymphocytes are a major source of beta-chemokines [3], but the stimulus for chemokine release has not been well defined. Here, we have shown that engagement of CD8+ cytotoxic T lymphocytes (CTLs) with HIV-1-encoded human leukocyte antigen (HLA) class I-restricted peptide antigens caused rapid and specific release of these beta-chemokines. This release paralleled cytolytic activity and could be attenuated by naturally occurring amino acid variation within the HLA class I-restricted peptide sequence. Epitope variants that bound to appropriate HLA class I molecules but failed to stimulate cytolytic activity in CTLs also failed to stimulate chemokine release. We conclude that signalling through the T-cell receptor (TCR) following binding of antigen results in beta-chemokine release from CTLs in addition to cytolytic activity, and that both responses can be abolished by epitope mutation. These results suggest that antigenic variation within HIV-1 might not only allow the host cell to escape lysis, but might also contribute to the propagation of infection by failing to activate beta-chemokine-mediated inhibition of HIV-1 entry.
Price
D A
DA
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Sewell
A K
AK
Dong
T
T
Tan
R
R
Goulder
P J
PJ
Rowland-Jones
S L
SL
Phillips
R E
RE
D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000302:isolation & purification; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000276:immunology; D002851:Chromatography, High Pressure Liquid; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000302:isolation & purification; D010455:Peptides / Q000276:immunology; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology
D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D019402:Macrophage Inflammatory Proteins; D010455:Peptides