Extended Data Fig. 5: The HIV-induced quiescence is triggered by a wide range of HIV strains and involves a marked downregulation of MYC and its downstream proliferative pathways.
From: HIV infection reprogrammes CD4+ T cells for quiescence and entry into proviral latency
a. The activity of a number of proliferation-inducing transcription factors, especially MYC, is strongly reduced in +HIV 72 hpi cells. Numbers between parentheses indicate the number of genes in each pathway that drive the enrichment phenotype (see Methods). b. Reads mapping to the genomic locus of MYC in Th17 cells during different stages in HIV and T cell life cycle. c. Temporal pattern of the gene expression changes occurring during the life cycle of HIV infected CD4 + T cells. The number of genes falling into early, late, and early+late categories is written above each box. Genes showing an overall pattern of down- and upregulation are shown in the left and right boxes, respectively. The expression values are graphed as log2 transformed transcript per million (TPM) values, with each line representing a gene. The line graphs indicate the level of expression of each gene in the four cellular states shown at the bottom of each column of line graphs. d. Pathway analysis results on genes in each category in panel c point to key roles for the p53 pathway and MYC signaling during early timepoints after HIV infection. e. Heatmap of the top differentially expressed genes in each category shown in panels c and d. The color bars to the left show the functional classification of each group of genes. f. Reads mapping to the genomic locus of E2F1 in Th17 cells during different stages in HIV and T cell life cycle. g. Pathway analysis using Hallmark gene lists on seven independently performed high throughput transcriptomic studies of CD4 + T cells in early time points after HIV infection point to MYC signaling as the most strongly downregulated pathway after HIV infection. The percentage of infected cells in the sequenced population of each dataset is indicated on top. N/A: not available. Cells used and time point of infection along with project accession numbers are shown at the bottom. The two primary HIV isolates studied in PRJNA482835 (STCO1 and CH077) are graphed separately. h. Primary purified CD4+ memory cells infected with five different HIV strains ex vivo show the downregulation of MYC, E2F and MTORC signaling along with elevated p53 activity, similar to results obtained using QUECEL models. Asterisks mark pathways differentially enriched concordantly in nearly all shown studies. CD4+ memory cells from three different donors were used in these studies. A similar analysis on a mixed CD4+ population using the NL4-3 HIV strain is also shown. i. Pathway analysis results indicate that in all four main subclasses of polarized effector T cells, HIV infection leads to the induction of the signature of entry into quiescence. Plus and minus signs at the bottom indicate positive and negative enrichment of pathways, respectively. j. Across multiple high throughput transcriptomic studies, HIV infection leads to strong and reproducible reduction and increase in the expression of MYC and KLF2, respectively. Milder downregulation of E2F family members is observed in some but not all studies. Please note that the Y axis is scaled differently for each of the stacked panels.
