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Two MHC Class I Molecules Associated with Elite Control of Immunodeficiency Virus Replication, Mamu-B*08 and HLA-B*2705, Bind Peptides with Sequence Similarity^1,2

John T. Loffredo^*, John Sidney, Alex T. Bean^*, Dominic R. Beal^*, Wilfried Bardet, Angela Wahl, Oriana E. Hawkins, Shari Piaskowski^*, Nancy A. Wilson^*, William H. Hildebrand, David I. Watkins^*, and Alessandro Sette^3,

^* Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706; Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715

HLA-B27- and -B57-positive HIV-infected humans have long been associated with control of HIV replication, implying that CD8⁺ T cell responses contribute to control of viral replication. In a similar fashion, 50% of Mamu-B*08-positive Indian rhesus macaques control SIVmac239 replication and become elite controllers with chronic-phase viremia <1000 viral RNA copies/ml. Interestingly, Mamu-B*08-restricted SIV-derived epitopes appeared to match the peptide binding profile for HLA-B*2705 in humans. We therefore defined a detailed peptide-binding motif for Mamu-B*08 and investigated binding similarities between the macaque and human MHC class I molecules. Analysis of a panel of 900 peptides revealed that despite substantial sequence differences between Mamu-B*08 and HLA-B*2705, the peptide-binding repertoires of these two MHC class I molecules share a remarkable degree of overlap. Detailed knowledge of the Mamu-B*08 peptide-binding motif enabled us to identify six additional novel Mamu-B*08-restricted SIV-specific CD8⁺ T cell immune responses directed against epitopes in Gag, Vpr, and Env. All 13 Mamu-B*08-restricted epitopes contain an R at the position 2 primary anchor and 10 also possess either R or K at the N terminus. Such dibasic peptides are less prone to cellular degradation. This work highlights the relevance of the Mamu-B*08-positive SIV-infected Indian rhesus macaque as a model to examine elite control of immunodeficiency virus replication. The remarkable similarity of the peptide-binding motifs and repertoires for Mamu-B*08 and HLA-B*2705 suggests that the nature of the peptide bound by the MHC class I molecule may play an important role in control of immunodeficiency virus replication.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease Grants N01-AI-40023, N01-AI-40024, and HHSN266200400006C (to A.S.), and HHSN266200400088C (to D.I.W.), as well as NIH Grants R01 AI049120, R01 AI052056, R24 RR015371, and R24 RR016038 (to D.I.W.). Additionally, this publication was made possible in part by Grant P51 RR000167 from the National Center for Research Resources, a component of the NIH, awarded to the Wisconsin National Primate Research Center, University of Wisconsin Madison. This work was conducted in part at a facility constructed with support from Research Facilities Improvement Program Grant nos. RR15459 and RR020141 (Wisconsin National Primate Research Center).

² This publication’s contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or National Institutes of Health.

³ Address correspondence and reprint requests to Dr. Alessandro Sette, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: alex{at}liai.org

⁴ Abbreviations used in this paper: EC, elite controller; PSCL, positional scanning combinatorial library; SF, specificity factor; SFC, spot-forming cell.

⁵ The online version of this article contains supplemental material.

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