Impaired CD4+ T cell differentiation in HIV-1 infected patients receiving early ART

Differentiation of CD4+ T naive (TN) into central memory (TCM) cells involves extensive molecular processes triggered by exposure to antigens. Recent WHO guidelines recommend antiretroviral therapy (ART) administration early during HIV-1 infection to avoid severe immunological complications. We compared the transcriptomes of CD4+ TN and TCM cells from early ART (EA) HIV-1 infected patients and matched controls (C).Total RNA was isolated from sorted blood CD4+ TN and TCM cells from 13 EA patients and 15 age-matched controls. The comparison of CD4+ TN with TCM cells transcriptomes revealed differentially expressed genes (DEGs) within and between cell populations. Data were analyzed for significant predictor genes and gene ontology (GO) term enrichment. A database of transcription factors (TFs) was assembled by merging publicly available information and TFs regulatory network with their target genes visualized. Published T helper cell gene sets were used to analyze T helper signatures of TCM.The comparison of protein coding genes between TCM and TN revealed 533 and 82 DEGs in C and EA, respectively. The most enriched GO term was 'cytokine mediated signaling pathway' in C and 'regulation of apoptotic process' in EA. A high degree of transcriptional complexity was detected during transition of CD4+ TN to TCM cells in controls involving over 70 TFs of which 20 are regulators of T cell differentiation (including TBX21, GATA3, RARA, FOXP3, RORC); in EA only 7 of 20 TFs were modulated with expression of GATA3, RARA, FOXP3, RORC remaining unchanged. Ten chemokine receptors important for homing CD4+ TCM cells to tissues were differentially expressed between TCM and TN cells of controls whereas only five were modulated in EA group. A network analysis of interactions between modulated TFs and target genes revealed that important regulatory interactions were missing in EA compared to control group.