Use of major histocompatibility complex class I/peptide/beta 2M tetramers to quantitate CD8(+) cytotoxic T lymphocytes specific for dominant and nondominant viral epitopes in simian-human immunodeficiency virus-infected rhesus monkeys

To evaluate the impact of the diversity of antigen recognition by T lymphoc ytes on disease pathogenesis, we must be able to identify and analyze simul taneously cytotoxic T-lymphocyte (CTL) responses specific for multiple vira l epitopes. Many of the studies of the role of CD8(+) CTLs in AIDS pathogen esis have been done with simian immunodeficiency virus (SN)- and simian-hum an immunodeficiency virus (SHIV)-infected rhesus monkeys. These studies hav e frequently made use of the well-defined SIV Gag CTL epitope p11C,C-M pres ented to CTL by the HLA-A homologue molecule Mamu-A*01. In the present stud y we identified and fine mapped two novel Mamu-A*01-restricted CTL epitopes : the SIVmac Pol-derived epitope p68A (STPPLVRLV) and the human immunodefic iency virus type 1 (HIV-1) Env-derived p41A epitope (YAPPISGQI). The freque ncy of CD8(+) CTLs specific for the p11C,CM, p68A, and p41A epitopes was qu antitated in the same animals with a panel of tetrameric Mamu-A*01/peptide/ beta 2m complexes. All SHIV-infected Mamu-A*01(+) rhesus monkeys tested Bad a high frequency of SIVmac Gag-specific CTLs to the p11C,C-M epitope. In c ontrast, only a fraction of the monkeys tested had detectable CTLs specific for the SIVmac pol p68A and HIV-1 Env p4LA epitopes, and these responses w ere detected at very low frequencies. Thus, the p11C,C-M-specific CD8(+) CT L response Is dominant and the p4LA- and p68A-specific CD8(+) CTL responses are nondominant. These results indicate that (CD8(+) CTL responses to domi nant CTL epitopes can be readily quantitated with the tetramer technology; however, CD8(+) CTL responses to nondominant epitopes, due to the low frequ ency of these epitope-specific cells, may be difficult to detect and quanti tate by this approach.