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Journal of Virology, November 2009, p. 11514-11527, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01298-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Infection with "Escaped" Virus Variants Impairs Control of Simian Immunodeficiency Virus SIVmac239 Replication in Mamu-B*08-Positive Macaques ^,

Laura E. Valentine,^1, John T. Loffredo,^1, Alex T. Bean,¹ Enrique J. León,² Caitlin E. MacNair,² Dominic R. Beal,¹ Shari M. Piaskowski,¹ Yann C. Klimentidis,³ Simon M. Lank,² Roger W. Wiseman,² Jason T. Weinfurter,⁴ Gemma E. May,² Eva G. Rakasz,^1,2 Nancy A. Wilson,¹ Thomas C. Friedrich,^2,4 David H. O'Connor,^1,2 David B. Allison,³ and David I. Watkins^1,2*

Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, Madison, Wisconsin 53706,¹ Wisconsin National Primate Research Center, University of Wisconsin—Madison, Madison, Wisconsin 53715,² Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 35294,³ Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine, Madison, Wisconsin 53706⁴

Received 24 June 2009/ Accepted 20 August 2009

An understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08⁺) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8⁺ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8⁺ T-cell epitopes to investigate the contribution of epitope-specific CD8⁺ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08⁺ macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08⁺ macaques. The five most immunodominant Mamu-B*08-restricted CD8⁺ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08⁺ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08⁺ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8⁺ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08⁺ macaques.

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* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, 555 Science Dr., Madison, WI 53711. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail: watkins{at}primate.wisc.edu

Published ahead of print on 2 September 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

Laura E. Valentine and John T. Loffredo contributed equally to this work.

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Journal of Virology, November 2009, p. 11514-11527, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01298-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.