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Journal of Virology, December 2004, p. 13190-13196, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13190-13196.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Sequence Variation within the Dominant Amino Terminus Epitope Affects Antibody Binding and Neutralization of Human Immunodeficiency Virus Type 1 Tat Protein

Tracy J. Ruckwardt,1,{dagger} Ilia Tikhonov,1 Shannon Berg,1 Glen S. Hatfield,1 Angelika Chandra,2 Prakash Chandra,2 Bruce Gilliam,1 Robert R. Redfield,1 Robert C. Gallo,1 and C. David Pauza1*

Institute of Human Virology, University of Maryland Biotechnology Center, Baltimore, Maryland,1 Institute of Transfusion Medicine, Frankfurt University School of Medicine, Frankfurt, Germany2

Received 24 March 2004/ Accepted 19 July 2004

Tat is among the required regulatory genes of human immunodeficiency virus type 1 (HIV-1). Tat functions both within infected cells as a transcription factor and as an extracellular factor that binds and alters bystander cells. Some functions of extracellular Tat can be neutralized by immune serum or monoclonal antibodies. In order to understand the antibody response to Tat, we are defining antibody epitopes and the effects of natural Tat sequence variation on antibody recognition. The dominant Tat epitope in macaque sera is within the first 15 amino acids of the protein amino terminus. Together with a subdominant response to amino acids 57 to 60, these two regions account for most of the macaque response to linear Tat epitopes and both regions are also sites for the binding of neutralizing antibodies. However, the dominant and subdominant epitope sequences differ among virus strains, and this natural variation can preclude antibody binding and Tat neutralization. We also examined serum samples from 31 HIV-positive individuals that contained Tat binding antibodies; 23 of the 31 sera recognized the amino terminus peptide. Similar to binding in macaques, human antibody binding to the amino terminus was affected by variations at positions 7 and 12, sequences that are distinct for clade B compared to other viral clades. Tat-neutralizing antibodies to the dominant amino terminus epitope are affected by HIV clade variation.

* Corresponding author. Mailing address: Institute of Human Virology, University of Maryland Biotechnology Institute, 725 W. Lombard St., Room N546, Baltimore, MD 21201. Phone: (410) 706-1367. Fax: (410) 706-6212. E-mail: pauza{at}umbi.umd.edu.

{dagger} Present address: Vaccine Research Center, National Institutes of Health, Bethesda, Md.

Journal of Virology, December 2004, p. 13190-13196, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13190-13196.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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