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• W2137146513 abstract "The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B∗1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B∗5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B∗5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders. The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B∗1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B∗5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B∗5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders. Polymorphic human leukocyte antigen (HLA) class I molecules present pathogen-derived peptides to killer T cells mediating protective immunity (Margulies et al., 2008Margulies D.H. Natarajan K. Rossjohn J. McCluskey J. Major histocompatibility complex (MHC) molecules: Structure, function, and genetics.in: Paul W.E. Fundamental Immunology. Lippincott Williams and Wilkins, Philadelphia2008Google Scholar). However particular major histocompatibility complex-I (MHC-I) allotypes are much more strongly associated with inflammatory, autoimmune-like diseases than they are with protective immunity phenotypes in infectious disease (Margulies et al., 2008Margulies D.H. Natarajan K. Rossjohn J. McCluskey J. Major histocompatibility complex (MHC) molecules: Structure, function, and genetics.in: Paul W.E. Fundamental Immunology. Lippincott Williams and Wilkins, Philadelphia2008Google Scholar). The reason for this paradox is unclear, and the mechanisms by which certain MHC-I allotypes are associated with inflammatory diseases like ankylosing spondylitis, Behçet's disease, and birdshot retinopathy are not understood (Margulies et al., 2008Margulies D.H. Natarajan K. Rossjohn J. McCluskey J. Major histocompatibility complex (MHC) molecules: Structure, function, and genetics.in: Paul W.E. Fundamental Immunology. Lippincott Williams and Wilkins, Philadelphia2008Google Scholar). Recently, however, hypersensitivity to the reverse-transcriptase inhibitor abacavir has been strongly associated with HLA-B∗5701 (Hetherington et al., 2002Hetherington S. Hughes A.R. Mosteller M. Shortino D. Baker K.L. Spreen W. Lai E. Davies K. Handley A. Dow D.J. et al.Genetic variations in HLA-B region and hypersensitivity reactions to Abacavir.Lancet. 2002; 359: 1121-1122Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar, Mallal et al., 2002Mallal S. Nolan D. Witt C. Masel G. Martin A.M. Moore C. Sayer D. Castley A. Mamotte C. Maxwell D. et al.Association between presence of HLA-B∗5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor Abacavir.Lancet. 2002; 359: 727-732Abstract Full Text Full Text PDF PubMed Scopus (1145) Google Scholar, Martin et al., 2004Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. Carvalho F. Phillips E. Christiansen F.T. Purcell A.W. et al.Predisposition to Abacavir hypersensitivity conferred by HLA-B∗5701 and a haplotypic Hsp70-Hom variant.Proc. Natl. Acad. Sci. USA. 2004; 101: 4180-4185Crossref PubMed Scopus (408) Google Scholar), providing an opportunity to unravel the mechanism of at least this MHC-I disease association with the potential to understand other MHC-I associations. Multiorgan reactions to abacavir occur in approximately 2%–8% of patients with human immunodeficiency virus-I (HIV-1) infection (Cutrell et al., 2004Cutrell A.G. Hernandez J.E. Fleming J.W. Edwards M.T. Moore M.A. Brothers C.H. Scott T.R. Updated clinical risk factor analysis of suspected hypersensitivity reactions to Abacavir.Ann. Pharmacother. 2004; 38: 2171-2172Crossref PubMed Scopus (88) Google Scholar). Abacavir hypersensitivity syndrome (AHS) manifests systemically as a combination of fever, rash, malaise, nausea, vomiting, and diarrhea and has even been associated with death in rechallenged individuals (Hetherington et al., 2001Hetherington S. McGuirk S. Powell G. Cutrell A. Naderer O. Spreen B. Lafon S. Pearce G. Steel H. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor Abacavir.Clin. Ther. 2001; 23: 1603-1614Abstract Full Text PDF PubMed Scopus (352) Google Scholar). This constellation of symptoms has some of the features of a graft versus host-like cellular reaction. Indeed, there is strong evidence for an immunological basis of AHS reflected in the presence of infiltrating CD8+ T cells in the skin of patients with a rash (Phillips et al., 2002Phillips E.J. Sullivan J.R. Knowles S.R. Shear N.H. Utility of patch testing in patients with hypersensitivity syndromes associated with Abacavir.AIDS. 2002; 16: 2223-2225Crossref PubMed Scopus (121) Google Scholar) and the induction of elevated tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) in patient whole blood and/or mononuclear cells exposed to abacavir in vitro (Martin et al., 2007Martin A.M. Almeida C.A. Cameron P. Purcell A.W. Nolan D. James I. McCluskey J. Phillips E. Landay A. Mallal S. Immune responses to Abacavir in antigen-presenting cells from hypersensitive patients.AIDS. 2007; 21: 1233-1244Crossref PubMed Scopus (42) Google Scholar). Patients who have experienced AHS also have more active nonspecific cytokine production by T cells from peripheral blood (King et al., 2005King D. Tomkins S. Waters A. Easterbrook P.J. Thurmond L.M. Thorborn D.E. Raffi F. Kemeny D.M. Vyakarnam A. Intracellular cytokines may model immunoregulation of Abacavir hypersensitivity in HIV-infected subjects.J. Allergy Clin. Immunol. 2005; 115: 1081-1087Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). A cellular immune reaction to abacavir is further supported by the specificity of positive skin-patch tests for delayed-type hypersensitivity in patients with AHS (Phillips et al., 2005Phillips E.J. Wong G.A. Kaul R. Shahabi K. Nolan D.A. Knowles S.R. Martin A.M. Mallal S.A. Shear N.H. Clinical and immunogenetic correlates of Abacavir hypersensitivity.AIDS. 2005; 19: 979-981Crossref PubMed Scopus (138) Google Scholar). The association of AHS with the well-defined 57.1 major histocompatibility complex (MHC) haplotype encoding the MHC class I allotype (MHC-I), HLA-B∗5701, is very strong (Hetherington et al., 2002Hetherington S. Hughes A.R. Mosteller M. Shortino D. Baker K.L. Spreen W. Lai E. Davies K. Handley A. Dow D.J. et al.Genetic variations in HLA-B region and hypersensitivity reactions to Abacavir.Lancet. 2002; 359: 1121-1122Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar, Mallal et al., 2002Mallal S. Nolan D. Witt C. Masel G. Martin A.M. Moore C. Sayer D. Castley A. Mamotte C. Maxwell D. et al.Association between presence of HLA-B∗5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor Abacavir.Lancet. 2002; 359: 727-732Abstract Full Text Full Text PDF PubMed Scopus (1145) Google Scholar, Martin et al., 2004Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. Carvalho F. Phillips E. Christiansen F.T. Purcell A.W. et al.Predisposition to Abacavir hypersensitivity conferred by HLA-B∗5701 and a haplotypic Hsp70-Hom variant.Proc. Natl. Acad. Sci. USA. 2004; 101: 4180-4185Crossref PubMed Scopus (408) Google Scholar), especially when AHS is rigorously defined (Mallal et al., 2002Mallal S. Nolan D. Witt C. Masel G. Martin A.M. Moore C. Sayer D. Castley A. Mamotte C. Maxwell D. et al.Association between presence of HLA-B∗5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor Abacavir.Lancet. 2002; 359: 727-732Abstract Full Text Full Text PDF PubMed Scopus (1145) Google Scholar, Mallal et al., 2008Mallal S. Phillips E. Carosi G. Molina J.-M. Workman C. Tomazic J. Jägel-Guedes E. Rugina S. Kozyrev O. Cid J.F. HLA-B∗5701 screening for hypersensitivity to Abacavir (Study CNA106030).N. Engl. J. Med. 2008; 358: 568-579Crossref PubMed Scopus (1379) Google Scholar, Martin et al., 2004Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. Carvalho F. Phillips E. Christiansen F.T. Purcell A.W. et al.Predisposition to Abacavir hypersensitivity conferred by HLA-B∗5701 and a haplotypic Hsp70-Hom variant.Proc. Natl. Acad. Sci. USA. 2004; 101: 4180-4185Crossref PubMed Scopus (408) Google Scholar). Thus, for immunologically confirmed AHS in the PREDICT-1 clinical trial, HLA-B∗5701 was associated with a positive predictive value of 47.9% and a negative predictive value of 100% (Mallal et al., 2008Mallal S. Phillips E. Carosi G. Molina J.-M. Workman C. Tomazic J. Jägel-Guedes E. Rugina S. Kozyrev O. Cid J.F. HLA-B∗5701 screening for hypersensitivity to Abacavir (Study CNA106030).N. Engl. J. Med. 2008; 358: 568-579Crossref PubMed Scopus (1379) Google Scholar). The prevalence of AHS varies according to the genetic background of the population, probably because of ethnic variation in the phenotypic frequency of HLA-B∗5701 in some populations (Hughes et al., 2004aHughes A.R. Mosteller M. Bansal A.T. Davies K. Haneline S.A. Lai E.H. Nangle K. Scott T. Spreen W.R. Warren L.L. Roses A.D. Association of genetic variations in HLA-B region with hypersensitivity to Abacavir in some, but not all, populations.Pharmacogenomics. 2004; 5: 203-211Crossref PubMed Scopus (231) Google Scholar). For instance AHS is less common in African Americans, who are known to have higher frequency of HLA-B∗5801, HLA-B∗5702, and HLA-B∗5703 subtypes and a correspondingly lower frequency of HLA-B∗5701 than patients of European descent (Hughes et al., 2004aHughes A.R. Mosteller M. Bansal A.T. Davies K. Haneline S.A. Lai E.H. Nangle K. Scott T. Spreen W.R. Warren L.L. Roses A.D. Association of genetic variations in HLA-B region with hypersensitivity to Abacavir in some, but not all, populations.Pharmacogenomics. 2004; 5: 203-211Crossref PubMed Scopus (231) Google Scholar). Some population differences in the degree of association between AHS and HLA-B∗5701 may arise because reliance upon the clinical definition of AHS leads to overassignment of the syndrome, thus confounding the association with HLA-B∗5701, especially where this allotype is present at a low frequency (Hetherington et al., 2002Hetherington S. Hughes A.R. Mosteller M. Shortino D. Baker K.L. Spreen W. Lai E. Davies K. Handley A. Dow D.J. et al.Genetic variations in HLA-B region and hypersensitivity reactions to Abacavir.Lancet. 2002; 359: 1121-1122Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar, Mallal et al., 2008Mallal S. Phillips E. Carosi G. Molina J.-M. Workman C. Tomazic J. Jägel-Guedes E. Rugina S. Kozyrev O. Cid J.F. HLA-B∗5701 screening for hypersensitivity to Abacavir (Study CNA106030).N. Engl. J. Med. 2008; 358: 568-579Crossref PubMed Scopus (1379) Google Scholar, Martin et al., 2004Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. Carvalho F. Phillips E. Christiansen F.T. Purcell A.W. et al.Predisposition to Abacavir hypersensitivity conferred by HLA-B∗5701 and a haplotypic Hsp70-Hom variant.Proc. Natl. Acad. Sci. USA. 2004; 101: 4180-4185Crossref PubMed Scopus (408) Google Scholar, Sun et al., 2007Sun H.Y. Hung C.C. Lin P.H. Chang S.F. Yang C.Y. Chang S.Y. Chang S.C. Incidence of Abacavir hypersensitivity and its relationship with HLA-B∗5701 in HIV-infected patients in Taiwan.J. Antimicrob. Chemother. 2007; 60: 599-604Crossref PubMed Scopus (59) Google Scholar). Accordingly, it is an acknowledged best practice and is cost effective to carry out HLA-B∗5701 genotyping to prevent abacavir hypersensitivity (Hughes et al., 2004bHughes D.A. Vilar F.J. Ward C.C. Alfirevic A. Park B.K. Pirmohamed M. Cost-effectiveness analysis of HLA B∗5701 genotyping in preventing Abacavir hypersensitivity.Pharmacogenetics. 2004; 14: 335-342Crossref PubMed Scopus (243) Google Scholar). The mechanism of abacavir-induced hypersensitivity and the basis for its association with HLA-B∗5701 remain unknown but are likely to be important in understanding the basis of other MHC-I-associated disorders such as ankylosing spondylitis (HLA-B27), Behçet's disease (HLA-B51), and birdshot retinopathy (HLA-A29). Abacavir is a prodrug that is converted to the active compound, leading us to hypothesize that this process may create a neoantigen that triggers CD8+ T cell immunity in HLA-B∗5701-positive individuals. The peripheral-blood mononuclear cells (PBMCs) from two HIV-1-infected patients with a history of AHS and who were HLA-B∗5701-positive, were stimulated with abacavir (10 μg/mL) for 11 to 14 days in vitro to test our hypothesis. This is the optimal culture period for expansion of alloreactive and antigen-specific memory CD8+ T cells in cultures that are supplemented with Interleukin-2 (IL-2). At the completion of the culture period, the expanded T cells were restimulated for 6 hr in the presence and absence of abacavir with the HLA-B∗5701-transfected, MHC-I-deficient B lymphoblastoid cell line C1R as antigen-presenting cells (APCs). Responding T cells were then examined for their phenotype and the accumulation of intracellular cytokines (as depicted schematically in Figure S1 available online). CD8+ T cells from patients with AHS proliferated in response to abacavir over 13 days and were specifically activated to produce IFNγ and TNFα, in the restimulation phase of the assay (Figure 1). Notably, it was the CD8+ T cells that responded by making cytokines, whereas the CD4+ T cells were not activated under the same conditions. Similar results were obtained when autologous PBMCs were used as APCs (not shown). These findings raised the likelihood that abacavir-specific CD8+ T cells play a key role in the pathogenesis of AHS. Expansion of abacavir-specific CD8+ T cells from HIV-1-infected patients with AHS was comparable to the expansion observed for Epstein-Barr virus (EBV)-specific memory T cells or allogeneic stimulator cells (Mifsud et al., 2008Mifsud N.A. Purcell A.W. Chen W. Holdsworth R. Tait B.D. McCluskey J. Immunodominance hierarchies and gender bias in direct T(CD8)-cell alloreactivity.Am. J. Transplant. 2008; 8 (Published online December 18, 2007): 121-132https://doi.org/10.1111/j.1600-6143.2007.02044.xCrossref PubMed Scopus (27) Google Scholar), suggesting proliferation of a memory cell population. This was confirmed by ex vivo elispot studies on blood from patients with abacavir hypersensitivity syndrome in which abacavir-specific, IFNγ-producing cells were detected with frequencies of up to 700 spots per 106 PBMCs (Figure S2). In contrast to the presence of memory T cells in the circulation of abacavir-hypersensitive patients, we did not detect abacavir-specific IFNγ-producing cells in ex vivo Elispot analyses of PBMCs from abacavir-naive normal HLA-B∗5701-positive blood donors. However, we also examined T cell responses from abacavir-naive, HLA-B∗5701-positive blood donors after in vitro stimulation for 11–14 days by using the same protocol as in HIV-1-infected patients. CD8+ T cells from these healthy individuals also proliferated in vitro and were specifically activated by abacavir to make IFNγ and TNFα (Figure 2A) over a pharmacological range of abacavir concentrations (0.5-10 μg/mL or 1.8-36 μM), (Figure 2B). Extensive washing of the APC after loading with abacavir preserved T cell recognition, demonstrating that the response was APC dependent and not a direct interaction between the T cell and the drug. Abacavir-reactive CD8+ T cells from normal HLA-B∗5701-positive donors were also cytotoxic (Figure 2C). Importantly, these responses were only observed in HLA-B∗5701-positive individuals and could not be induced in individuals with any of the other MHC-I backgrounds we tested (Figures 2C and 2D). Nonetheless, EBV-specific CD8+ T cell responses were readily elicited in HLA-B∗5701-negative donors when a cocktail of known viral peptides was used to restimulate the T cells (right panel, Figure 2D). Abacavir-specific CD8+ T cells were not activated by C1R.B57 loaded with a peptide derived from an EBV latent membrane protein (LMP), IALYLQQNW (IALY) (Duraiswamy et al., 2003Duraiswamy J. Burrows J.M. Bharadwaj M. Burrows S.R. Cooper L. Pimtanothai N. Khanna R. Ex vivo analysis of T-cell responses to Epstein-Barr virus-encoded oncogene latent membrane protein 1 reveals highly conserved epitope sequences in virus isolates from diverse geographic regions.J. Virol. 2003; 77: 7401-7410Crossref PubMed Scopus (45) Google Scholar) (not shown). CD8+ T responses within each individual were entirely restricted by the HLA-B∗5701 allotype despite expression of non-HLA-B∗5701 MHC-I allotypes in these donors, (Figure 2E and not shown). Thus, abacavir-reactive T cells from three different donors were rechallenged with abacavir-loaded APCs expressing their individual MHC-I allotypes (e.g., for donor 1, HLA A2, HLA A29, and HLA B57). T cell recognition of abacavir occurred only when the cells were stimulated with HLA-B∗5701-postive APCs, (Figure 2E, randomized-block ANOVA p < 0.001). In summary, abacavir-specific CD8+ T responses were uniquely HLA-B∗5701 restricted in HLA-B∗5701- positive individuals, and these responses could not be elicited in HLA-B∗5701-negative donors expressing seven common HLA-A allotypes (HLA-A1, 2, 3, 11, 24, 29, and 68) and nine common HLA-B allotypes (HLA-B7, 8, 18, 27, 35, 44, 45, 65, and 62). Moreover, abacavir-specific, HLA-B∗5701-restricted CD8+ T cells did not react with abacavir-loaded APCs expressing 11 different allogeneic MHC-I allotypes (not shown). Thus HLA-B∗5701 restriction is a defining feature of abacavir-specific T cells isolated from abacavir-naive individuals. Abacavir-specific CD8+ T cells interacted conventionally with HLA-B∗5701 because cytokine responses were partially blocked by addition of a Bw4, HLA-B∗5701-reactive mAb, but not when the non-HLA-B∗5701-reactive Bw6 mAb was added to the T cell cultures (Figure 2F). We observed that in vitro cultures from patients with AHS generated a greater proportion of specific CD8+ T cells than similar cultures from naive donors, consistent with CD8+ T cell memory in the patients. Nonetheless, abacavir-specific T cells from both groups were exclusively CD8+, HLA-B∗5701-restricted, produced TNFα and IFNγ, and were sensitive to abacavir over a dose-response range that includes the serum concentration of abacavir in treated patients. We conclude that the abacavir-specific, HLA-B∗5701-restricted CD8+ T cells generated in normal blood donors are similar in their specificity and nature to the abacavir-reactive T cells detected in patients with AHS. Therefore, we used responses from normal HLA-B∗5701-positive donors to probe the biology and specificity of these abacavir-specific responses. In the MHC-I-restricted antigen-presentation pathway, endogenous peptide ligands are created in the cytoplasm by proteolysis and then imported into the endoplasmic reticulum by the transporter associated with antigen presentation (TAP) (McCluskey et al., 2004McCluskey J. Rossjohn J. Purcell A.W. TAP genes and immunity.Curr. Opin. Immunol. 2004; 16: 651-659Crossref PubMed Scopus (46) Google Scholar) where peptide loading is optimized by the chaperone, tapasin (Williams et al., 2002bWilliams A.P. Peh C.A. Purcell A.W. McCluskey J. Elliott T. Optimization of the MHC class I peptide cargo is dependent on tapasin.Immunity. 2002; 16: 509-520Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). Functional loss of either TAP or tapasin leads to defective peptide loading and impaired antigen presentation (Williams et al., 2002aWilliams A. Peh C.A. Elliott T. The cell biology of MHC class I antigen presentation.Tissue Antigens. 2002; 59: 3-17Crossref PubMed Scopus (103) Google Scholar). However, the MHC-I antigen-presentation pathway can be bypassed by the addition of exogenous peptide ligands to either living or aldehyde-fixed APCs through direct loading of ligand-receptive MHC-I molecules on the cell surface. Such complexes are capable of recognition by antigen-specific T cells (Figure 3A). However, when abacavir was added to aldehyde-fixed, HLA-B∗5701-positive APCs, it did not reconstitute a ligand that could stimulate abacavir-specific CD8+ T cells (Figure 3A), indicating a need for live APCs to mediate intracellular processing or modification of the drug to create a ligand (Figure 3A). This finding was reproducible in multiple experiments (n = 7) and statistically significant (p < 0.001, Tukey HSD multiple comparison following logarithmic transformation of the data). Mutant HLA-B∗5701-positive APCs in which TAP function was impaired by coexpression of the viral TAP inhibitor ICP47 also did not present abacavir to specific CD8+ T cells generated in four different donors (Figure 3B, upper panel). Exogenous loading of TAP-blocked APC with a HLA-B∗5701-restricted EBV peptide resulted in efficient recognition by specific antiviral CD8+ T cells in the same donors (Figure 3B, lower panel). Similarly, presentation of abacavir was substantially reduced by the mutant tapasin-deficient cell line 721.220 expressing HLA-B∗5701 (Figure 3C). When tapasin expression was restored in these cells by gene transfection, presentation of abacavir was also restored (Figure 3C). Presentation of abacavir to CD8+ T cells was also impaired by pretreatment of APC with the antifungal agent Brefeldin A, which disrupts egress of newly synthesized and antigen-loaded MHC-I molecules from the endoplasmic reticulum to the cell surface (not shown). Taken together, these findings indicated that abacavir recognition depends upon the conventional MHC-I antigen-presentation pathway and demonstrate that the unmodified prodrug is insufficient to form a T cell ligand by direct cell-surface MHC-I loading. HLA-B∗5701 is part of the serologically defined HLA-B17 allotypic family that includes naturally occurring variants HLA-B∗5702 and HLA-B∗5801, which differ from HLA-B∗5701 by only three and four amino acids, respectively (Figure 4A). Indeed, these closely related MHC-I allotypes have significant overlap in their peptide repertoire (Barber et al., 1997Barber L.D. Percival L. Arnett K.L. Gumperz J.E. Chen L. Parham P. Polymorphism in the alpha 1 helix of the HLA-B heavy chain can have an overriding influence on peptide-binding specificity.J. Immunol. 1997; 158: 1660-1669PubMed Google Scholar), and many virus-specific T cells are crossreactive with all three MHCp complexes (Duraiswamy et al., 2003Duraiswamy J. Burrows J.M. Bharadwaj M. Burrows S.R. Cooper L. Pimtanothai N. Khanna R. Ex vivo analysis of T-cell responses to Epstein-Barr virus-encoded oncogene latent membrane protein 1 reveals highly conserved epitope sequences in virus isolates from diverse geographic regions.J. Virol. 2003; 77: 7401-7410Crossref PubMed Scopus (45) Google Scholar). However, abacavir-loaded lymphoblastoid cell lines expressing these allotypes did not stimulate polyclonal abacavir-specific, HLA-B∗5701-restricted CD8+ T cells from six independent donors (Figures 4A and 4B). Nonetheless, in four of these donors, there was crossreactivity of HLA-B∗5701-restricted antiviral CD8+ T cells on peptide-loaded HLA-B∗5702 and HLA-B∗5801 APCs (Figure 4B). The mutations that distinguish HLA-B∗5702 and HLA-B∗5801 from HLA-B∗5701 are predominantly located in the antigen-binding cleft (Figure 4A). Notably, HLA-B∗5801 differs at residues 97 and 103 as well as residues 45 and 46, which form the B pocket anchor site. In contrast, HLA-B∗5702 differs at position 156 and residues 114 and 116, the latter of which forms the F pocket anchor site (Figure 4A). Accordingly, the failure of HLA-B∗5801 and HLA-B∗5702 to stimulate CD8+ T cells suggests the abacavir-related ligand is either presented in an altered conformation or is not presented at all by these MHC-I allotypes because of the altered chemical structure of their antigen-binding cleft. The latter seems more likely, given the lack of any association between AHS and these or any other MHC-I allotypes. Despite the overlap in peptide repertoire of the B17 allotypic group, HLA-B∗5701 prefers a lysine residue as the optimal residue of the bound peptide at position 3, whereas HLA-B∗5702 prefers an aspartic acid in this position (Barber et al., 1997Barber L.D. Percival L. Arnett K.L. Gumperz J.E. Chen L. Parham P. Polymorphism in the alpha 1 helix of the HLA-B heavy chain can have an overriding influence on peptide-binding specificity.J. Immunol. 1997; 158: 1660-1669PubMed Google Scholar). Hence, the amino acid substitutions between HLA-B∗5701 and HLA-B∗5702 at positions 114 (D→N), 116 (S→Y), and 156 (L→R) could influence abacavir recognition via selection of amino acids at P3, the C terminus, or both. To determine whether the loss of abacavir presentation by HLA-B∗5702 could arise entirely from the substitutions at 114 (D→N) and 116 (S→Y), we made these two substitutions by site-directed mutagenesis, thus creating the natural allotypic variant, HLA-B∗5703. abacavir-loaded C1R cells expressing the HLA-B∗5703 molecule did not stimulate abacavir-specific CD8+ T cells, indicating that substitution of F pocket residues 114 and 116 was sufficient to impair presentation of the abacavir-related ligand (Figure 5, second panel). The impact of individually changing residues 114 and 116 was then examined. Substitution of residue 114 from a negatively charged aspartate in HLA-B∗5701 to a neutrally charged asparagine in HLA-B∗5703 (D→N) resulted in a > 50% reduction in the number of IFNγ-producing CD8+ T cells and lower levels of IFNγ production by the remaining responding cells (Figure 5, third panel). Substitution of position 116, from a polar serine in HLA-B∗5701 to the aromatic tyrosine residue of HLA-B∗5703 (S→Y), completely abrogated recognition by abacavir-specific CD8+ T cells (Figure 5, fourth panel). Position 116 is particularly important in determining the structure of the F pocket and thus controls selection of the dominant anchor residue at the C terminus of bound peptides (Gomez et al., 2006Gomez P. Montserrat V. Marcilla M. Paradela A. de Castro J.A. B∗2707 differs in peptide specificity from B∗2705 and B∗2704 as much as from HLA-B27 subtypes not associated to spondyloarthritis.Eur. J. Immunol. 2006; 36: 1867-1881Crossref PubMed Scopus (30) Google Scholar, Zernich et al., 2004Zernich D. Purcell A.W. Macdonald W.A. Kjer-Nielsen L. Ely L.K. Laham N. Crockford T. Mifsud N.A. Bharadwaj M. Chang L. et al.Natural HLA class I polymorphism controls the pathway of antigen presentation and susceptibility to viral evasion.J. Exp. Med. 2004; 200: 13-24Crossref PubMed Scopus (131) Google Scholar). The repertoire of peptides bound by HLA- HLA-B∗5701, HLA-B∗5702, and HLA-B∗5801 allotypes share a preference for tryptophan or a phenylalanine at position 9 in the F pocket (Barber et al., 1997Barber L.D. Percival L. Arnett K.L. Gumperz J.E. Chen L. Parham P. Polymorphism in the alpha 1 helix of the HLA-B heavy chain can have an overriding influence on peptide-binding specificity.J. Immunol. 1997; 158: 1660-1669PubMed Google Scholar). However, only HLA-B∗5701 is reported to also accommodate a tyrosine in this position, indicating that the F pocket polymorphism results in selection of a different subset of endogenous ligands by HLA-B∗5701 (Barber et al., 1997Barber L.D. Percival L. Arnett K.L. Gumperz J.E. Chen L. Parham P. Polymorphism in the alpha 1 helix of the HLA-B heavy chain can have an overriding influence on peptide-binding specificity.J. Immunol. 1997; 158: 1660-1669PubMed Google Scholar) as observed for other MHC-I allotypes (Kubo et al., 1998Kubo H. Ikeda-Moore Y. Kikuchi A. Miwa K. Nokihara K. Schonbach C. Takiguchi M. Residue 116 determines the C-terminal anchor residue of HLA-B∗3501 and -B∗5101 binding peptides but does not explain the general affinity difference.Immunogenetics. 1998; 47: 256-263Crossref PubMed Scopus (18) Google Scholar, Ramos et al., 2002Ramos M. Paradela A. Vazquez M. Marina A. Vazquez J. Lopez de Castro J.A. Differential association of HLA-B∗2705 and B∗2709 to ankylosing spondylitis correlates with limited peptide subsets but not with altered cell surface stability.J. Biol. Chem. 2" @default.
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