Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children

doi:10.1128/JVI.74.12.5679-5690.2000

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Journal of Virology, June 2000, p. 5679-5690, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children

Philip J. R. Goulder,¹^,²^,^* C. Brander,¹ K. Annamalai,³ N. Mngqundaniso,³ U. Govender,³ Y. Tang,¹ S. He,¹ K. E. Hartman,¹ C. A. O'Callaghan,⁴ G. S. Ogg,⁴ M. A. Altfeld,¹ E. S. Rosenberg,¹ H. Cao,¹ S. A. Kalams,¹ M. Hammond,⁵ M. Bunce,⁶ S. I. Pelton,⁷ S. A. Burchett,² K. McIntosh,² H. M. Coovadia,³ and B. D. Walker¹

Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129¹; Division of Infectious Diseases, The Children's Hospital,² and Section of Pediatric Infectious Diseases, Boston Medical Center,⁷ Boston, Massachusetts 02118; Department of Paediatrics, University of Natal,³ and Natal Blood Transfusion Service, Pinetown,⁵ Durban, South Africa; and MRC Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU,⁴ and Oxford Transplant Centre, Churchill Hospital, Oxford OX3 7LJ,⁶ United Kingdom

Received 11 January 2000/Accepted 28 March 2000

Cytotoxic T-lymphocyte (CTL) activity plays a central role in control of viral replication and in determining outcome in casesof human immunodeficiency virus type 1 (HIV-1) infection. Incorporationof important CTL epitope sequences into candidate vaccines is,therefore, vital. Most CTL studies have focused upon small numbersof adult Caucasoid subjects infected with clade-B virus, whereasthe global epidemic is most severe in sub-Saharan African populationsand predominantly involves clade-C infection in both adults andchildren. In this study, sensitive enzyme-linked immunospot (elispot)assays have been utilized to identify the dominant Gag-specificCTL epitopes targeted by adults and children infected with clade-Bor -C virus. Cohorts evaluated included 44 B-clade-infected CaucasoidAmerican and African American adults and children and 37 C-clade-infectedAfrican adults and children from Durban, South Africa. The resultsshow that 3 out of 46 peptides spanning p17^Gag and p24^Gag sequences tested contain two-thirds of the dominant Gag-specificepitopes, irrespective of the clade, ethnicity, or age group studied.However, there were distinctive differences between the dominantresponses made by Caucasoids and Africans. Dominant responsesin Caucasoids were more often within p17^Gag peptide residues 16 to 30 (38 versus 12%; P < 0.01), while p24^Gag peptide residues 41 to 60 contained the dominant Gag epitopemore often in the African subjects tested (39 versus 4%; P < 0.005).Within this 20-mer p24^Gag, an epitope presented by both B42 and B81 is defined which representsthe dominant Gag response in >30% of the total infected populationin Durban. This epitope is closely homologous with dominant HIV-2and simian immunodeficiency virus Gag-specific CTL epitopes. Thefine focusing of dominant CTL responses to these few regions ofhigh immunogenicity is of significance to vaccinedesign.

^* Corresponding author. Mailing address: Partners AIDS Research Center, Massachusetts General Hospital, 13th St., Bldg. 149,Rm. 5218, Charlestown, MA 02129. Phone: (617) 726-5787. Fax: (617)726-5411. E-mail: goulder{at}helix.mgh.harvard.edu.

Journal of Virology, June 2000, p. 5679-5690, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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