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Antagonist HIV-1 Gag peptides induce structural changes in HLA B8.

Reid SW, McAdam S, Smith KJ, Klenerman P, O'Callaghan CA, Harlos K, Jakobsen BK, McMichael AJ, Bell JI, Stuart DI, Jones EY - J. Exp. Med. (1996)

Bottom Line: McMichael. 1994.Nature (Lond.). 369:403-407).While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biophysics, Oxford, United Kingdom. SCOTT@BIOP.OX.AC.UK

ABSTRACT
In the cellular immune response, recognition by CTL-TCRs of viral antigens presented as peptides by HLA class I molecules, triggers destruction of the virally infected cell (Townsend, A.R.M., J. Rothbard, F.M. Gotch, G. Bahadur, D. Wraith, and A.J. McMichael. 1986. Cell. 44:959-968). Altered peptide ligands (APLs) which antagonise CTL recognition of 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 of antigen presenting cells by CTLs in response to recognition of an HLA B8-restricted HIV-1 P17 (aa 24-31) epitope can be inhibited by naturally 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 with these variants of P17 (aa 24-31) exhibit a variety of responses. We have examined the high resolution crystal structures of four of these APLs in complex with HLA B8 to determine alterations in the shape, chemistry, and local flexibility of the TCR binding surface. The variant peptides cause changes in the recognition surface by three mechanisms: changes contributed directly by the peptide, effects transmitted to the exposed peptide surface, and induced effects on the exposed framework of the peptide binding groove. While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.

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CTL recognition and antagonism by naturally occurring p17 variants. Recognition of variant peptides by two donor 008 clones (18 and 20)  (a and b) at an ET of 8:1. (c) Inhibition of killing by clone 20, at an ET of 8:1, by the 3R and 5R variants shown to be encoded for by this provirus (5).  Gag p24 (residues 261–269, GEIYKRWII) was used as a control HLA-B8 restricted peptide. (d ) Inhibition of killing by line 84, at an ET of 4:1, by 7R  and 7Q. Influenza nuclear protein (residues 380–388, ELRSRYWAI) was used as a HLA B8 restricted control peptide.
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Figure 1: CTL recognition and antagonism by naturally occurring p17 variants. Recognition of variant peptides by two donor 008 clones (18 and 20) (a and b) at an ET of 8:1. (c) Inhibition of killing by clone 20, at an ET of 8:1, by the 3R and 5R variants shown to be encoded for by this provirus (5). Gag p24 (residues 261–269, GEIYKRWII) was used as a control HLA-B8 restricted peptide. (d ) Inhibition of killing by line 84, at an ET of 4:1, by 7R and 7Q. Influenza nuclear protein (residues 380–388, ELRSRYWAI) was used as a HLA B8 restricted control peptide.

Mentions: Residues 24–31 (GGKKKYKL) of the HIV-1 Gag protein p17, a region overlapping the nuclear localization site (1), have been mapped as an HLA B8–restricted epitope capable of eliciting a CTL response in HIV-1 seropositive individuals (2). Variations in the genetic sequence encoding these residues have been detected in viruses isolated from patients making a CTL response to this epitope (2, 3). Our present study focuses on four peptides which are related to the index peptide (GGKKKYKL) by single residue changes corresponding to naturally occurring variant epitope sequences, each of which has occured in more than one HLA B8 positive, HIV infected patient (Table 1, denoted as 3R, 5R, 7R, and 7Q). The index and variant peptides bind HLA B8 with similar affinities in vitro (4). A number of CTL clones and lines specific for this epitope have been generated from two HIV positive donors. Fig. 1 shows data from two clones and a line demonstrating the effects that these substitutions can have in terms of recognition and antagonism. The differences between the index and the four variant HLA B8–peptide complexes have been analysed in a series of x-ray crystallographic structure determinations at 2.3 Å resolution or better. Crystallographic statistics for each of the complexes are detailed in Table 1. In line with the binding motif deduced from several epitopes and pooled peptide sequences (5), the index peptide (residues P1–P8) is anchored in the HLA B8–binding groove by buried lysine residues at peptide positions P3 and P5 and by the COOHterminal (P8 or PC) leucine residue (see Fig. 2). Conversely, the sidechains of residues P4, P7 and P6, contribute to the surface exposed for TCR recognition. The APLs thus encompass changes at residues directly exposed to TCR recognition (P7) and at buried anchor residues (P3 and P5).


Antagonist HIV-1 Gag peptides induce structural changes in HLA B8.

Reid SW, McAdam S, Smith KJ, Klenerman P, O'Callaghan CA, Harlos K, Jakobsen BK, McMichael AJ, Bell JI, Stuart DI, Jones EY - J. Exp. Med. (1996)

CTL recognition and antagonism by naturally occurring p17 variants. Recognition of variant peptides by two donor 008 clones (18 and 20)  (a and b) at an ET of 8:1. (c) Inhibition of killing by clone 20, at an ET of 8:1, by the 3R and 5R variants shown to be encoded for by this provirus (5).  Gag p24 (residues 261–269, GEIYKRWII) was used as a control HLA-B8 restricted peptide. (d ) Inhibition of killing by line 84, at an ET of 4:1, by 7R  and 7Q. Influenza nuclear protein (residues 380–388, ELRSRYWAI) was used as a HLA B8 restricted control peptide.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196387&req=5

Figure 1: CTL recognition and antagonism by naturally occurring p17 variants. Recognition of variant peptides by two donor 008 clones (18 and 20) (a and b) at an ET of 8:1. (c) Inhibition of killing by clone 20, at an ET of 8:1, by the 3R and 5R variants shown to be encoded for by this provirus (5). Gag p24 (residues 261–269, GEIYKRWII) was used as a control HLA-B8 restricted peptide. (d ) Inhibition of killing by line 84, at an ET of 4:1, by 7R and 7Q. Influenza nuclear protein (residues 380–388, ELRSRYWAI) was used as a HLA B8 restricted control peptide.
Mentions: Residues 24–31 (GGKKKYKL) of the HIV-1 Gag protein p17, a region overlapping the nuclear localization site (1), have been mapped as an HLA B8–restricted epitope capable of eliciting a CTL response in HIV-1 seropositive individuals (2). Variations in the genetic sequence encoding these residues have been detected in viruses isolated from patients making a CTL response to this epitope (2, 3). Our present study focuses on four peptides which are related to the index peptide (GGKKKYKL) by single residue changes corresponding to naturally occurring variant epitope sequences, each of which has occured in more than one HLA B8 positive, HIV infected patient (Table 1, denoted as 3R, 5R, 7R, and 7Q). The index and variant peptides bind HLA B8 with similar affinities in vitro (4). A number of CTL clones and lines specific for this epitope have been generated from two HIV positive donors. Fig. 1 shows data from two clones and a line demonstrating the effects that these substitutions can have in terms of recognition and antagonism. The differences between the index and the four variant HLA B8–peptide complexes have been analysed in a series of x-ray crystallographic structure determinations at 2.3 Å resolution or better. Crystallographic statistics for each of the complexes are detailed in Table 1. In line with the binding motif deduced from several epitopes and pooled peptide sequences (5), the index peptide (residues P1–P8) is anchored in the HLA B8–binding groove by buried lysine residues at peptide positions P3 and P5 and by the COOHterminal (P8 or PC) leucine residue (see Fig. 2). Conversely, the sidechains of residues P4, P7 and P6, contribute to the surface exposed for TCR recognition. The APLs thus encompass changes at residues directly exposed to TCR recognition (P7) and at buried anchor residues (P3 and P5).

Bottom Line: McMichael. 1994.Nature (Lond.). 369:403-407).While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biophysics, Oxford, United Kingdom. SCOTT@BIOP.OX.AC.UK

ABSTRACT
In the cellular immune response, recognition by CTL-TCRs of viral antigens presented as peptides by HLA class I molecules, triggers destruction of the virally infected cell (Townsend, A.R.M., J. Rothbard, F.M. Gotch, G. Bahadur, D. Wraith, and A.J. McMichael. 1986. Cell. 44:959-968). Altered peptide ligands (APLs) which antagonise CTL recognition of 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 of antigen presenting cells by CTLs in response to recognition of an HLA B8-restricted HIV-1 P17 (aa 24-31) epitope can be inhibited by naturally 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 with these variants of P17 (aa 24-31) exhibit a variety of responses. We have examined the high resolution crystal structures of four of these APLs in complex with HLA B8 to determine alterations in the shape, chemistry, and local flexibility of the TCR binding surface. The variant peptides cause changes in the recognition surface by three mechanisms: changes contributed directly by the peptide, effects transmitted to the exposed peptide surface, and induced effects on the exposed framework of the peptide binding groove. While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.

Show MeSH
Related in: MedlinePlus