File:Hivlatency.jpg

English: F2: Reactivation of HIV-1 transcriptional latency. During latency, nuc-1 blocks transcriptional initiation and/or elongation, Tat is absent and only short mRNAs corresponding to TAR are produced. Nuc-1 is maintained hypoacethylated by HDACs recruited to the 5’LTR via several transcription factor (YY1, CTIP-2, p50-p50 homodimer, CBF-1). The corepressor CTIP-2 interacts with the Sp1 transcription factor at three sites in the HIV-1 5’ LTR and recruits HDACs and the HMT Suv39h1, which trimethylates H3K9 leading to the recruitment of HP1. Other histone methylation repressive marks such as H3K9Me2 or H3K27Me3 catalyzed by the HMT G9a and EZH2, respectively, are also implicated in HIV-1 latency. In addition, during latency, the HIV-1 promoter is hypermethylated at two CpG islands surrounding the HIV-1 transcriptional start site. The dotted arrows indicate that DNMTs are most likely recruited to the HIV-1 promoter but this recruitment has not been demonstrated so far. In latent conditions, the active form of NF-kappaB (p50-p65 heterodimers) is sequestered in the cytoplasm by the inhibitor of nuclear factor kappaB (IκB), while NF-kappaB p50-p50 homodimers occupies the kappaB sites at the viral LTR region. The kappaB sites can also be occupied by CBF-1 and by STAT5Δ/p50 heterodimer in monocytic cells. The phosphorylated form of NFAT is also in the cytoplasm in latency conditions. Moreover, in resting CD4+ T cells, P-TEFb, composed of CDK9 and human cyclin T1, is sequestered in an inactive form by the HEXIM-1/7SK snRNA regulatory complex. In this context, several compounds have been proposed for trasncriptionalreactiation of HIV-1 including HDACIs (SAHA, VPA) to target the hypoacetylated state of nuc-1, HMTIs (chaetocin, BIX-01294, DZNEP) to target HMTs, DNMTIs (5-Aza-CdR) to target 5’LTR DNA methylation, PKC or Akt agonists (sprostratin, bryostatin) to activate the NF-kappaB signaling pathway, cytokines (IL-2, IL-7, GM-CSF) to activate STAT5 and inducers of P-TEFb release (HMBA, JQ1).