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Journal of Virology, August 2003, p. 9029-9040, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.9029-9040.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Major Histocompatibility Complex Class I Alleles Associated with Slow Simian Immunodeficiency Virus Disease Progression Bind Epitopes Recognized by Dominant Acute-Phase Cytotoxic-T-Lymphocyte Responses

David H. O'Connor,1 Bianca R. Mothe,1 Jason T. Weinfurter,1 Sarah Fuenger,1 William M. Rehrauer,1 Peicheng Jing,1 Richard R. Rudersdorf,1 Max E. Liebl,1 Kendall Krebs,1 Joshua Vasquez,1 Elizabeth Dodds,1 John Loffredo,1 Sarah Martin,1 Adrian B. McDermott,1 Todd M. Allen,1 Chenxi Wang,2 G. G. Doxiadis,3 David C. Montefiori,4 Austin Hughes,5 Dennis R. Burton,6 David B. Allison,2 Steven M. Wolinsky,7 Ronald Bontrop,3 Louis J. Picker,8 and David I. Watkins1*

Wisconsin Regional Primate Research Center and Department of Pathology and Laboratory Medicine, Madison, Wisconsin,1 University of Alabama at Birmingham, Birmingham, Alabama,2 Duke University Department of Experimental Surgery, Durham, North Carolina,4 University of South Carolina, Columbia, South Carolina,5 The Scripps Research Institute, La Jolla, California,6 Northwestern University Medical School, Chicago, Illinois,7 Oregon Health & Science University Vaccine and Gene Therapy Institute, Portland, Oregon,8 Biomedical Primate Research Centre-TNO, Rijswijk, The Netherlands3

Received 24 February 2003/ Accepted 9 May 2003

Certain major histocompatibility complex class I (MHC-I) alleles are associated with delayed disease progression in individuals infected with human immunodeficiency virus (HIV) and in macaques infected with simian immunodeficiency virus (SIV). However, little is known about the influence of these MHC alleles on acute-phase cellular immune responses. Here we follow 51 animals infected with SIVmac239 and demonstrate a dramatic association between Mamu-A*01 and -B*17 expression and slowed disease progression. We show that the dominant acute-phase cytotoxic T lymphocyte (CTL) responses in animals expressing these alleles are largely directed against two epitopes restricted by Mamu-A*01 and one epitope restricted by Mamu-B*17. One Mamu-A*01-restricted response (Tat28-35SL8) and the Mamu-B*17-restricted response (Nef165-173IW9) typically select for viral escape variants in early SIVmac239 infection. Interestingly, animals expressing Mamu-A*1 and -B*17 have less variation in the Tat28-35SL8 epitope during chronic infection than animals that express only Mamu-A*01. Our results show that MHC-I alleles that are associated with slow progression to AIDS bind epitopes recognized by dominant CTL responses during acute infection and underscore the importance of understanding CTL responses during primary HIV infection.

* Corresponding author. Mailing address: Department of Pathology, 1300 University Ave., Madison, WI 53706. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail: watkins{at}primate.wisc.edu.

Journal of Virology, August 2003, p. 9029-9040, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.9029-9040.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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