Complete mapping of a novel HLA A*6801-restricted HIV-1 Tat epitope directly ex vivo with a rapid modified enzyme-linked immunospot assay

Oxenius, Annette; Jakobsen, Bent K.; Easterbrook, Philippa; Boulter, Jonathan M.; Tun, Tin A.; Waters, Anele; Agudelo, Juliet; Barnardo, Martin; Phillips, Rodney E.; Price, David A.

doi:10.1097/00002030-200206140-00012

Cited by 4 publications

(10 citation statements)

References 10 publications

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“…Val residue at position 67 may provide a more capacious B pocket able to accommodate somewhat larger aliphatic residues. At the F pocket (where the C-terminal position [PC] of the epitope is accommodated), HLA-A*7401 is identical to HLA-A*3301, -A*6601, and -A*6801 (Table III, bottom half ), predicting preferential binding of the basic residues Arg or Lys (27, 33, 39). …”

Section: Resultsmentioning

confidence: 99%

HLA-A7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B5703

Matthews

Adland

Listgarten³

et al. 2011

The Journal of Immunology

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The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade–infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401–restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401–restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.

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Section: Resultsmentioning

confidence: 99%

HLA-A7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B5703

Matthews

Adland

Listgarten³

et al. 2011

The Journal of Immunology

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“…Residue 2 and the C‐terminal residue act as anchors for HLA‐A68 11. Neither of the two 10‐mer peptides contained within the 11‐mer ITKGLGISYGR epitope were antigenic 18. Consequently, this HIV‐1 Tat‐derived peptide is longer than normal MHCI‐presented peptides and is expected to bulge out from the HLA‐A68 α1/α2 peptide‐binding platform.…”

Section: Resultsmentioning

confidence: 99%

“…We manufactured two mutated forms of HLA‐A68 in order to increase or abrogate CD8 binding. We have previously examined CD8 binding to HLA‐A68 13, 18. WT HLA‐A68 binds CD8 with low affinity (KD=980 μM) 13.…”

Section: Resultsmentioning

confidence: 99%

Functional and biophysical characterization of an HLA‐A*6801‐restricted HIV‐specific T cell receptor

Gostick¹,

Cole²,

Hutchinson³

et al. 2007

Eur J Immunol

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HLA-A*6801 exhibits several unusual features. First, it is known to bind weakly to CD8 due to the presence of an A245V substitution in the α3 domain. Second, it is able to accommodate unusually long peptides as a result of peptide ‘kinking’ in the binding groove. Third, CD8+ cytotoxic T lymphocytes that recognise HLA-A*6801-restricted antigens can tolerate substantial changes in the peptide sequence without apparent loss of recognition. In addition, it has been suggested that HLA-A68-restricted TCR might bind with higher affinity than other TCR due to their selection in the presence of a decreased contribution from CD8. Here we (1) examine monoclonal T cell recognition of an HLA-A*6801-restricted HIV-1 Tat-derived 11-amino acid peptide (ITKGLGISYGR) and natural variant sequences thereof; (2) measure the affinity and kinetics of a TCR/pHLA-A68 interaction biophysically for the first time, showing that equilibrium binding occurs within the range previously determined for non-HLA-A68-restricted TCR (KD approx. 7 μM); and (3) show that “normalization” of the non-canonical HLA-A*6801 CD8-binding domain enhances recognition of agonist peptides without inducing non-specific activation. This latter effect may provide a fundamental new mechanism with which to enhance T cell immunity to specific antigens.

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“…HLA A2 heavy chains were refolded with the HIV p17 Gag epitope SLYNTVATL (residues 77-85) or the influenza matrix protein GILGFVFTL (residues 58 -66). HLA A68 heavy chain was refolded with the HIV-1 Tat epitope ITKGLGISYGR (37). Following buffer exchange into 10 mM Tris, pH 8.1, refolded monomer was purified by anion exchange.…”

Section: Methodsmentioning

confidence: 99%

“…6A). C1R HLA A68 and C1R HLA D227K/T228A A68 were used to present antigen to HLA A68-restricted CTL specific for a HIV-1 Tat epitope (ITKGLGISYGR) (37). D227K/T228A HLA A68-expressing cells were impaired in their ability to activate a HLA A68restricted, HIV-1 ITKGLGISYGR-specific CTL clone (c23) (Fig.…”

Section: Generation and Validation Of Pmhci And ␤ 2 M Mutationsmentioning

confidence: 99%

The CD8 T Cell Coreceptor Exhibits Disproportionate Biological Activity at Extremely Low Binding Affinities

Hutchinson

Wooldridge

Tafuro

et al. 2003

Journal of Biological Chemistry

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112

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T lymphocytes recognize peptides presented in the context of major histocompatibility complex (MHC) molecules on the surface of antigen presenting cells. Recognition specificity is determined by the alphabeta T cell receptor (TCR). The T lymphocyte surface glycoproteins CD8 and CD4 enhance T cell antigen recognition by binding to MHC class I and class II molecules, respectively. Biophysical measurements have determined that equilibrium binding of the TCR with natural agonist peptide-MHC (pMHC) complexes occurs with KD values of 1-50 microm. The pMHCI/CD8 and pMHCII/CD4 interactions are significantly weaker than this (KD >100 microm), and the relative roles of TCR/pMHC and pMHC/coreceptor affinity in T cell activation remain controversial. Here, we engineer mutations in the MHCI heavy chain and beta2-microglobulin that further reduce or abolish the pMHCI/CD8 interaction to probe the significance of pMHC/coreceptor affinity in T cell activation. We demonstrate that the pMHCI/CD8 coreceptor interaction retains the vast majority of its biological activity at affinities that are reduced by over 15-fold (KD > 2 mm). In contrast to previous reports, we observe that the weak interaction between HLA A68 and CD8, which falls within this spectrum of reduced affinities, retains substantial functional activity. These findings are discussed in the context of current concepts of coreceptor dependence and the mechanism by which TCR coreceptors facilitate T cell activation.

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Complete mapping of a novel HLA A*6801-restricted HIV-1 Tat epitope directly ex vivo with a rapid modified enzyme-linked immunospot assay

Cited by 4 publications

References 10 publications

HLA-A7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B5703

HLA-A7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B5703

Functional and biophysical characterization of an HLA‐A*6801‐restricted HIV‐specific T cell receptor

The CD8 T Cell Coreceptor Exhibits Disproportionate Biological Activity at Extremely Low Binding Affinities

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Complete mapping of a novel HLA A*6801-restricted HIV-1 Tat epitope directly ex vivo with a rapid modified enzyme-linked immunospot assay

Cited by 4 publications

References 10 publications

HLA-A*7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B*5703

HLA-A*7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B*5703

Functional and biophysical characterization of an HLA‐A*6801‐restricted HIV‐specific T cell receptor

The CD8 T Cell Coreceptor Exhibits Disproportionate Biological Activity at Extremely Low Binding Affinities

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HLA-A7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B5703

HLA-A7401–Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B5703