ANTIGEN-SPECIFIC RELEASE OF BETA-CHEMOKINES BY ANTI-HIV-1 CYTOTOXIC T-LYMPHOCYTES

A major advance in understanding human immunodeficiency virus (HIV) bi ology was the discovery that the beta-chemokines MIP-1 alpha (macropha ge inflammatory protein-1 alpha), MIP-1 beta (macrophage inflammatory protein-1 beta) and RANTES (regulated on activation, normal T-cell exp ressed and secreted) inhibit entry of HIV-1 into CD4(+) cells by block ing the critical interaction between the CCR5 coreceptor and the V3 do main of the viral envelope glycoprotein gp120 [1,2]. CD8(+) lymphocyte s are a major source of beta-chemokines [3], but the stimulus for chem okine release has not been well defined. Here, we have shown that enga gement of CD8(+) cytotoxic T lymphocytes (CTLs) with HIV-1-encoded hum an leukocyte antigen (HLA) class I-restricted peptide antigens caused rapid and specific release of these beta-chemokines. This release para lleled cytolytic activity and could be attenuated by naturally occurri ng amino acid variation within the HLA class I-restricted peptide sequ ence. Epitope variants that bound to appropriate HLA class I molecules but failed to stimulate cytolytic activity in CTLs also failed to sti mulate chemokine release, We conclude that signalling through the T-ce ll receptor (TCR) following binding of antigen results in beta-chemoki ne 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 ce ll to escape lysis, but might also contribute to the propagation of in fection by failing to activate beta-chemokine-mediated inhibition of H IV-1 entry. (C) Current Biology Ltd ISSN 0960-9822.