The functional impairment and numerical decline of CD8+ T cells during HIV infection has a profound effect on disease progression, but only limited microarray studies have used CD8+ T cells. To understand the interactions of HIV and host CD8+ T cells at different disease status, we used the Illumina Human-6 BeadChips to evaluate the transcriptional profile (>48,000 transcripts) in primary CD8+ T cells from HIV+ therapy-naive non-progressors and therapy-experienced progressors. 68 differentially expressed genes were identified, of which 6 have been reported in HIV context, while others are associated with biological functions relevant to HIV pathogenesis. By GSEA, the coordinated up-regulation of oxidative phosphorylation enzymes and interferon responses were detected as fingerprints in HIV progressors on HAART, whereas LTNP displayed a transcriptional signature of coordinated up-regulation of components of MAPK and cytotoxicty pathways. These results will provide biological insights into natural control of HIV versus HIV control under HAART.