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Journal of Virology, June 2008, p. 5245-5254, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00292-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Comprehensive Immunological Evaluation Reveals Surprisingly Few Differences between Elite Controller and Progressor Mamu-B*17-Positive Simian Immunodeficiency Virus-Infected Rhesus Macaques{triangledown}

Nicholas J. Maness,1 Levi J. Yant,1 Chungwon Chung,1 John T. Loffredo,1 Thomas C. Friedrich,1 Shari M. Piaskowski,2 Jessica Furlott,1 Gemma E. May,1 Taeko Soma,1 Enrique J. León,1 Nancy A. Wilson,1 Helen Piontkivska,3 Austin L. Hughes,4 John Sidney,5 Alessandro Sette,5 and David I. Watkins1,2*

Wisconsin National Primate Research Center,1 Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, Madison, Wisconsin 53711,2 Department of Biological Sciences, Kent State University, Kent, Ohio 44242,3 Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208,4 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 920375

Received 8 February 2008/ Accepted 25 March 2008

The association between particular major histocompatibility complex class I (MHC-I) alleles and control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication implies that certain CD8+ T-lymphocyte (CD8-TL) responses are better able than others to control viral replication in vivo. However, possession of favorable alleles does not guarantee improved prognosis or viral control. In rhesus macaques, the MHC-I allele Mamu-B*17 is correlated with reduced viremia and is overrepresented in macaques that control SIVmac239, termed elite controllers (ECs). However, there is so far no mechanistic explanation for this phenomenon. Here we show that the chronic-phase Mamu-B*17-restricted repertoire is focused primarily against just five epitopes—VifHW8, EnvFW9, NefIW9, NefMW9, and envARFcRW9—in both ECs and progressors. Interestingly, Mamu-B*17-restricted CD8-TL do not target epitopes in Gag. CD8-TL escape variation occurred in all targeted Mamu-B*17-restricted epitopes. However, recognition of escape variant peptides was commonly observed in both ECs and progressors. Wild-type sequences in the VifHW8 epitope tended to be conserved in ECs, but there was no evidence that this enhances viral control. In fact, no consistent differences were detected between ECs and progressors in any measured parameter. Our data suggest that the narrowly focused Mamu-B*17-restricted repertoire suppresses virus replication and drives viral evolution. It is, however, insufficient in the majority of individuals that express the "protective" Mamu-B*17 molecule. Most importantly, our data indicate that the important differences between Mamu-B*17-positive ECs and progressors are not readily discernible using standard assays to measure immune responses.

* 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

{triangledown} Published ahead of print on 2 April 2008.

Journal of Virology, June 2008, p. 5245-5254, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00292-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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