GENOMIC BASIS OF CD8-MEDIATED PROTECTION: CLUES FROM THE WHOLE HUMAN GENOME MICROARRAY STUDIES
It is already known that the functional impairment and numerical decline of CD8+ T cells during HIV infection has a profound effect on disease progression, but to date, only limited microarray studies have used cellular transcriptome of CD8+ T cells in order to understand the interactions of HIV and host CD8+ T cells at different disease status.
Previous microarray studies in relation to HIV disease have used whole PBMC or cell lines, monocytes, macrophages, CD4+ T cells, lymphoid and gut tissue, etc [99, 100], but only a few studies have used CD8+ T cells to understand gene regulation during HIV infection. These include studies using CD8+ T cell gene expression profiling to detect genes responsible for non-cytotoxic activity of CD8+ T cells [101, 102]; the study by Martinez-Marino et al. identified 52 differentially expressed genes between infected subjects with high CD8+ cell non-cytotoxic anti-HIV responses and uninfected controls that lack this activity. Recently, the transcriptional profiling of CD4+ and CD8+ T cells from early infection, chronic infection and LTNP patients has been studied and interferon responses were characterized as a transcriptional signature of T cells from early and chronic HIV infected individuals [103]. It has also been shown that CD8+ T cells contain more differential genes than CD4+ T cells, which is consistent with our recent antibody microarray study illustrating that CD8+ T cells have more cell surface molecules differentiating disease status then CD4+ T cells [104].Our recent studies [105] assessed all 48,000 human genome transcripts (encompassing all 25,000 human genes) in primary CD8+ T cells from HIV+ therapy naive non-progressors and therapy-experienced progressors. Sixty-eight differentially expressed genes were identified and divided into eight categories according to their biological functions and relevance in HIV pathogenesis: (1) genes previously reported to be involved in HIV infection and disease (6/68); (2) Interferon induced, apoptosis and actin-related genes (11/68); (3) cell cycle, proliferation and activation genes (5/68); (4) adhesion and cell surface molecules (6/68); (5) endosome, lysosome and cytotoxicity (6/68); (6) mitochondria, lipid and carbohydrate metabolism associated genes (8/68); (7) genes lacking relevance to HIV pathogenesis (13/68) and (8) less characterized genes (13/68). Further, by geneset enrichment analysis (GSEA), the coordinated up-regulation of oxidative phosphorylation genes encoding for enzymes and genes involved in interferon responses were detected as fingerprints in HIV progressors on HAART, whereas LTNPs displayed a transcriptional signature of coordinated up-regulation of components of MAPK pathway.