PATTERNS OF IMMUNODOMINANCE IN HIV-1-SPECIFIC CYTOTOXIC T-LYMPHOCYTE RESPONSES IN 2 HUMAN HISTOCOMPATIBILITY LEUKOCYTE ANTIGENS (HLA)-IDENTICAL SIBLINGS WITH HLA-A-ASTERISK-0201 ARE INFLUENCED BY EPITOPE MUTATION

Primary human immunodeficiency virus (HIV) infection is controlled pri ncipally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-sta te 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 repor t describes the CTL responses of two HLA-identical hemophiliac brother s who were exposed to identical batches of Factor VIII and became sero positive within 10 wk of one another. Both have HLA-A0201. The CTL re sponses of the two siblings were very dissimilar, one donor making str ong responses to two epitopes within p17 Gag (HLA-A0201-restricted SL YNTVATL and HLA-A3-restricted RLRPGGKKK). The sibling responded to nei ther epitope, but made strong responses to two epitopes presented by H LA-B7. This was not the result of differences in presentation of the e pitopes. 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-A0201-restricted epitop es, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected do nors with HLA-A0201. The majority (71%) generated responses to the Ga g epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL res ponses using peptide stimulation of PBMC, and most of these donors als o showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that muta tion in immunodominant epitopes can profoundly alter the pattern of CT L response.