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Journal of Virology, December 2003, p. 12430-12440, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12430-12440.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of Sequential Viral Escape Mutants Associated with Altered T-Cell Responses in a Human Immunodeficiency Virus Type 1-Infected Individual

Mark J. Geels,1 Marion Cornelissen,1 Hanneke Schuitemaker,2,3 Kiersten Anderson,4 David Kwa,2,3 Jolanda Maas,5 John T. Dekker,5 Elly Baan,1 Fokla Zorgdrager,1 Remco van den Burg,1 Martijn van Beelen,1 Vladimir V. Lukashov,1 Tong-Ming Fu,4 William A. Paxton,1 Lia van der Hoek,1 Sheri A. Dubey,4 John W. Shiver,4 and Jaap Goudsmit6*

Department of Human Retrovirology, Academic Medical Center,1 Sanquin Research at CLB,2 Landsteiner Laboratory at AMC, University of Amsterdam,3 PrimaGen,5 Center for Poverty-Related Communicable Diseases, Amsterdam, The Netherlands,6 Department of Virus and Cell Biology, Merck Research Laboratories, West Point, Pennsylvania4

Received 29 April 2003/ Accepted 11 August 2003

Control of viremia in natural human immunodeficiency virus type 1 (HIV-1) infection in humans is associated with a virus-specific T-cell response. However, still much is unknown with regard to the extent of CD8+ cytotoxic T-lymphocyte (CTL) responses required to successfully control HIV-1 infection and to what extent CTL epitope escape can account for rises in viral load and ultimate progression to disease. In this study, we chose to monitor through full-length genome sequence of replication-competent biological clones the modifications that occurred within predicted CTL epitopes and to identify whether the alterations resulted in epitope escape from CTL recognition. From an extensive analysis of 59 biological HIV-1 clones generated over a period of 4 years from a single individual in whom the viral load was observed to rise, we identified the locations in the genome of five CD8+ CTL epitopes. Fixed mutations were identified within the p17, gp120, gp41, Nef, and reverse transcriptase genes. Using a gamma interferon ELIspot assay, we identified for four of the five epitopes with fixed mutations a complete loss of T-cell reactivity against the wild-type epitope and a partial loss of reactivity against the mutant epitope. These results demonstrate the sequential accumulation of CTL escape in a patient during disease progression, indicating that multiple combinations of T-cell epitopes are required to control viremia.

* Corresponding author. Present address: Crucell, Archimedesweg 4, P.O. Box 2048, 2301 CA Leiden, The Netherlands. Phone: 31-71-5248-755. Fax: 31-71-5248-853. E-mail: J.Goudsmit{at}crucell.com.

Journal of Virology, December 2003, p. 12430-12440, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12430-12440.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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