Antigen–specific release of β-chemokines by anti-HIV-1 cytotoxic T lymphocytes

Abstract

A major advance in understanding human immunodeficiency virus (HIV) biology was the discovery that the β-chemokines MIP-1α (macrophage inflammatory protein-1α), MIP-1β (macrophage inflammatory protein-1β) 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 β-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 β-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 β-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 β-chemokine-mediated inhibition of HIV-1 entry.