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Structural basis of diverse peptide accommodation by the rhesus macaque MHC class I molecule Mamu-B*17: insights into immune protection from simian immunodeficiency virus

Wu, Y., Gao, F., Liu, J., Qi, J., Gostick, E., Price, David and Gao, G. F. 2011. Structural basis of diverse peptide accommodation by the rhesus macaque MHC class I molecule Mamu-B*17: insights into immune protection from simian immunodeficiency virus. The Journal of Immunology 187 (12) , pp. 6382-6392. 10.4049/jimmunol.1101726

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Abstract

The MHC class I molecule Mamu-B*17 has been associated with elite control of SIV infection in rhesus macaques, akin to the protective effects described for HLA-B*57 in HIV-infected individuals. In this study, we determined the crystal structures of Mamu-B*17 in complex with eight different peptides corresponding to immunodominant SIVmac239-derived CD8+ T cell epitopes: HW8 (HLEVQGYW), GW10 (GSHLEVQGYW), MW9 (MHPAQTSQW), QW9 (QTSQWDDPW), FW9 (FQWMGYELW), MF8 (MRHVLEPF), IW9 (IRYPKTFGW), and IW11 (IRYPKTFGWLW). The structures reveal that not only P2, but also P1 and P3, can be used as N-terminal anchor residues by Mamu-B*17–restricted peptides. Moreover, the N-terminal anchor residues exhibit a broad chemical specificity, encompassing basic (H and R), bulky polar aliphatic (Q), and small (T) residues. In contrast, Mamu-B*17 exhibits a very narrow preference for aromatic residues (W and F) at the C terminus, similar to that displayed by HLA-B*57. Flexibility within the whole peptide-binding groove contributes to the accommodation of these diverse peptides, which adopt distinct conformations. Furthermore, the unusually large pocket D enables compensation from other peptide residues if P3 is occupied by an amino acid with a small side chain. In addition, residues located at likely TCR contact regions present highly flexible conformations, which may impact TCR repertoire profiles. These findings provide novel insights into the structural basis of diverse peptide accommodation by Mamu-B*17 and highlight unique atomic features that might contribute to the protective effect of this MHC I molecule in SIV-infected rhesus macaques. The development of an effective vaccine against HIV infection and AIDS is a global public health priority. Accordingly, there has been much scientific focus on SIV infection of nonhuman primates, especially rhesus macaques, which provides a useful model to inform HIV pathogenesis and study the efficacy of vaccine candidates (1, 2). In the past decade, most work on SIV-specific CD8+ T cell responses in the rhesus macaque model has centered on the MHC class I (MHC I) molecule Mamu-A*01 (3–20). More recently, however, the scope of immunological studies in this model has expanded to include additional MHC I molecules that display distinct biological properties. Mamu-B*17, which is present in >12% of captive Indian rhesus macaques (21), is associated with the control of SIV replication in vivo (22–26), although it should be noted that inheritance of this allele alone does not predict a favorable outcome and that the immunological basis for this association remains unclear. In humans, it is well-established that HLA-B*27 and HLA-B*57, the gene products of which present HIV-derived epitopes that elicit highly effective CD8+ T cell responses (27–31), are associated with reduced virus loads and delayed disease progression in HIV-infected individuals (27, 32–35). By analogy, the study of Mamu-B*17–positive rhesus macaques provides an opportunity to understand how specific MHC I molecules might impact AIDS virus replication in a controlled setting (31). The peptide-binding specificity of Mamu-B*17 has been identified, together with a range of presented SIV-derived epitopes that exhibit diverse lengths and antigenicities (36). Strikingly, no immunodominant Gag-derived epitopes have been described (36). In contrast, many targeted epitopes emanate from the smaller regulatory/accessory proteins Nef and Vif (Table I) (37). Given the critical roles of these proteins with respect to infectivity and pathogenicity, such epitopes may be appealing targets for vaccine development. CD8+ T cell responses restricted by Mamu-B*17 can be detected during both the acute and chronic phases of SIV infection (36), which suggests that this MHC I molecule could play important roles in the control of viral replication throughout the course of infection. However, the efficacy of immunodominant CD8+ T cell responses can be impaired by the selection of viral escape variants (38). Indeed, the emergence of escape mutations frequently correlates directly with the loss of viral suppression (38–40). Nevertheless, this phenomenon can impact viral fitness and reflects the potency of certain CD8+ T cell response (41). Many escape mutations within viral epitopes involve anchor residue substitutions that impede peptide binding to the corresponding MHC I molecule. In contrast, much of the observed sequence variation within Mamu-B*17–restricted epitopes does not seem to impair peptide–MHC I (pMHC I) binding substantially (42). Moreover, in the Mamu-B*17 setting, the C-terminal tryptophan anchor residues remain conserved, and amino acid substitutions only rarely affect the N-terminal anchors at positions 1, 2, or 3. Although variants of the HW8 epitope (Vif66–73) can display substitutions in the N-terminal anchor residue, they maintain the ability to bind Mamu-B*17, which likely reflects amino acid compatibility and pocket B flexibility. Similarly, the Ile-to-Thr replacement at the N-terminal amino acid residue of the IW9 epitope (Nef165–173) does not impact either Mamu-B*17 binding or CD8+ T cell recognition; rather, this mutation hinders Ag processing and/or presentation (42). Collectively, these features indicate that Mamu-B*17–restricted epitopes are favorable targets for effective CD8+ T cell immunity. Indeed, Mamu-B*17+ elite controllers (ECs) have been shown to resist rechallenge with variant SIV strains containing multiple escape mutations, and CD8+ T cell clones derived from ECs were more effective at suppressing viral replication than those derived from progressors (43). The characteristics of peptide presentation by MHC I play a pivotal role in the antigenicity of an epitope (44–49). Accordingly, we determined the structures of eight SIVmac239-derived epitopes in complex with Mamu-B*17 to define the atomic basis for effective epitope presentation by this protective MHC I molecule. Structural analysis revealed a novel peptide-binding strategy for the accommodation of diverse antigenic peptides, which informs our understanding of the association between Mamu-B*17 and the control of SIV replication.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology
Publisher: American Association of Immunologists
ISSN: 0022-1767
Date of First Compliant Deposit: 9 March 2017
Date of Acceptance: 5 October 2011
Last Modified: 04 Jun 2017 09:44
URI: http://orca.cf.ac.uk/id/eprint/98873

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