Impairment of Gag-specific CD8(+) T-cell function in mucosal and systemic compartments of simian immunodeficiency virus mac251-and simian-human immunodeficiency virus KU2-infected macaques

The identification of several simian immunodeficiency virus mac251 (SIVmac2 51) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infecte d rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-ma jor histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8( +) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell respo nse in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissue s of eight Mamu-A*01-positive macaques, six of those infected with SIVmac25 1 and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 1 81), since it was predominant in most tissues of all macaques. Five macaque s restricted viral replication effectively, whereas the remaining three fai led to control viremia and experienced a progressive loss of CD4(+) T cells . The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from di fferent animals. We found that the functionality of this virus-specific CD8 (+) T-cell population could not be assumed based on the ability to specific ally bind to the Gag 181 tetramer, particularly in the mucosal tissues of s ome of the macaques infected by SIVmac251 that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues a ssessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low a nd was even lower in the mucosal tissue than in blood or spleen of some SIV mac251-infected animals that failed to control viremia. The data obtained i n this pilot study lead to the hypothesis that disease progression may be a ssociated with loss of virus-specific CD8(+) T-cell function.