Systems biology applications to study mechanisms of human immunodeficiency virus latency and reactivation

Figure 4 Main findings from gene expression studies using Latency reversing agents. A: Novel mechanisms of HIV reactivation besides primary mechanisms of action of LRAs. These include upregulation (red arrow) of HIV activators (red oval) and downregulation (blue arrow) of repressors (blue oval). Examples for LRAs from 3 functional classes (HDACi, SAHA; PKC agonist, Prostratin; and bromodomain inhibitor, JQ1) are listed; B: Effects of LRAs on host genes that are inhibitory for HIV reactivation. These include upregulation (red arrow) of HIV repressors (blue oval) and downregulation (blue arrow) of activators (red oval). Examples for LRAs from 2 functional classes (HDACi, SAHA; and PKC agonist, Prostratin) are shown; C: LRAs of different classes act on components of p-TEFb complex via different mechanisms, contributing to HIV reactivation. SAHA induced dissociation of p-TEFb from the inactive 7SK RNA complex and facilitated its recruitment to the HIV LTR. Prostrain and JQ1 upregulated components of p-TEFb complex at the protein and RNA level, respectively (red arrows indicate upregulation). LRA: Latency reversing agent; HDACi: Histone deacetylase inhibitor; PKC: Protein kinase C; SAHA: Suberoylanilide hydroxamic acid; IGRM: Immunity-related GTPase family, M; HSPA2: Heat shock 70 kDA protein 2; KDM1A: Lysine (K)-specific demethylase; TNFSF4: Tumor necrosis factor (ligand) superfamily, member 4; RCOR1: REST coreceptor 1; SIRT1: Sirtuin 1; AES: Amino-terminal enhancer of split; ARID1B: AT rich interactive domain 1B, SWI1-like; DEFA1: Defensin alpha 1; PRMT6: Protein arginine methyltransferase 6; SETDB1: SET domain, bifurcated 1; ETS1: V-Ets avian erythroblastosis virus E26 oncogene homolog 1; LEF1: Lymphoid enhancer-binding factor 1; HMGA1: High mobility group AT-hook 1; HIVEP3: HIV type I enhancer binding protein 3; EZH2: Enhancer of zeste 2 polycomb repressive complex 2 subunit; YY1: YY1 transcription factor; BRD2: Bromodomain protein containing 2; S100A8: S100 Calcium Binding Protein A8; S100A9: S100 Calcium Binding Protein A9; S100A12: S100 Calcium Binding Protein A12; CDK9: Cyclin-dependent kinase 9; P-TEFb: Positive transcription elongation factor; CycT1: Cyclin T1; Hexim-1: Hexamethylene Bis-Acetamide Inducible 1; LTR: Long terminal repeat; Tat: Transactivator of transcription.