J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/04/1423/06 $2.00
Volume 185, Number 8, April 21, 1997 1423-1433

Patterns of Immunodominance in HIV-1-specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation

By P.J.R. Goulder,^* A.K. Sewell,^* D.G. Lalloo,^* D.A. Price,^* J.A. Whelan,^* J. Evans, G.P. Taylor,^§ G. Luzzi,^¶ P. Giangrande, R.E. Phillips,^* and A.J. McMichael^*

From the ^* Molecular Immunology Group, Nuffield Department of Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom;  Department of Paediatrics, Queen Elizabeth Queen Mother Wing, St. Mary's Hospital, London W2 1NY, United Kingdom; ^§ Department of Genito-Urinary Medicine, St Mary's Hospital, London W2 1NY, United Kingdom; ^¶ Department of Genito-Urinary Medicine, Wycombe General Hospital, South Buckinghamshire NHS Trust, High Wycombe Bucks, HP11 2TT, United Kingdom; and the  Oxford Haemophilia Centre, Churchill Hospital, Oxford OX3 7LJ, United Kingdom

Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201-restricted SLYNTVATL and HLA-A3-restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201-restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.

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