ANTAGONIST HIV-1 GAG PEPTIDES INDUCE STRUCTURAL-CHANGES IN HLA B8

In the cellular immune response, recognition by CTL-TCRs of viral anti gens presented as peptides by HLA class I molecules, triggers destruct ion of the virally infected cell (Townsend, A.R.M., J. Rothbard, F.M. Gotch, G. Bahadur, D. Wraith, and A.J. McMichael. 1986. Cell. 44:959-9 68). Altered peptide ligands (APLs) which antagonise CTL recognition o f infected cells have been reported (Jameson, S.C., F.R. Carbone, and M.J. Bevan. 1993. J. Exp. Med. 177:1541-1550). In one example, lysis o f antigen presenting cells by CTLs in response to recognition of an HL A B8-restricted HIV-1 P17 (aa 24-31) epitope can be inhibited by natur ally occurring variants of this peptide, which act as TCR antagonists (Klenerman, P., S. Rowland Jones, S. McAdam, J. Edwards, S. Daenke, D. Lalloo, B. Koppe, W. Rosenberg, D. Boyd, A. Edwards, P. Giangrande, R .E. Phillips, and A. McMichael. 1994. Nature (Lond.). 369:403-407). We have characterised two CTL clones and a CTL line whose interactions w ith these variants of P17 (aa 24-31) exhibit a variety of responses. W e have examined the high resolution crystal structures of four of thes e APLs in complex with HLA B8 to determine alterations in the shape, c hemistry, and local flexibility of the TCR binding surface. The varian t peptides cause changes in the recognition surface by three mechanism s: changes contributed directly by the peptide, effects transmitted to the exposed peptide surface, and induced effects on the exposed frame work of the peptide binding groove. While the first two mechanisms fre quently lead to antagonism, the third has more profound effects on TCR recognition.