CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency

Abstract

The establishment of HIV proviral latency requires the creation of repressive chromatin structures that impair the initiation of transcription and restrict RNAP II elongation. We have found that C‐promoter binding factor‐1 (CBF‐1), a CSL (CBF‐1, Su(H) and Lag‐1)‐type transcription factor and key effector of the Notch signaling pathway, is a remarkably potent and specific inhibitor of the HIV‐1 LTR promoter. Knockdown of endogenous CBF‐1 using specific small hairpin RNAs expressed on lentiviral vectors results in the partial reactivation of latent HIV proviruses, recruitment of RNAP II, loss of histone deacetylases and the concomitant acetylation of histones. An important property of any repressor utilized to establish HIV latency is that it must become displaced or deactivated upon T‐cell activation. Consistent with this hypothesis, CBF‐1 mRNA and protein levels are highest in quiescent or unstimulated T cells but decline rapidly in response to proliferative stimulation such as activation of the T‐cell receptor or treatment with TNF‐α. We conclude that CBF‐1 is a previously overlooked factor that induces transcriptional silencing during the establishment of HIV latency.

Reactivation of Latent HIV-1 Infection by the Periodontopathic Bacterium Porphyromonas gingivalis Involves Histone Modification

“…For example, LSF binds YY1 which recruits transcriptional corepressor HDAC1, thus maintaining the transcriptional latency (12). However, other transcription factors binding to the adjacent regions of Nuc-1, such as AP-4 (14), p50 homodimers (13), C-promoter binding factor-1 (15), and Sp1-cMyc complex (16), are known to recruit HDAC proteins leading to transcriptional silencing. Upon stimulation of cells such as by TNF-␣, transcriptional activators including NF-B are recruited together with coactivators exhibiting histone acetyltransferase (HAT) activity.…”

“…In contrast to productively infected cells, latently infected cells harboring HIV-1 genomes integrated into heterochromatin structures that allow persistence of transcriptionally silent proviruses (9,10). Hyperacetylation of core histone proteins adjacent to the HIV-1 provirus was correlated with transcriptional activation from HIV-1 LTR (5, 6, 11), whereas hypoacetylation mediated by HDAC was correlated with its repression (12)(13)(14)(15)(16). For example, we reported that AP-4 acts as a transcriptional repressor by recruiting HDAC molecules and is involved in the maintenance of viral latency (14).…”

“…On the other hand, HIV-1 viral latency is maintained by transcriptional factors such as Yin Yang (YY)-1, p50 homodimer, C-promoter binding factor-1, c-Myc, and AP-4 which in turn recruit HDAC proteins into the vicinity of HIV-1 proviral DNA (12)(13)(14)(15)(16). Thus, it is possible that the effect of csp could be through the inhibition of HDAC.…”

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir

“…Thus, class 1 HDACs are recruited to the proviral DNA, in proximity to nuc-1, through the action of DNA binding proteins. Nuclear factor (NF)-κB p50 homodimer, activating enhancer binding protein 4 (AP-4), retinoblastoma-family protein 2 (RBF2), as well as c-Myc and specificity protein 1 (SP-1) recruit class I HDACs to the LTR, which in turn results in deacetylation of local histones, compaction of the chromatin and prevention of RNA polymerase II binding (25,(27)(28)(29)(30)(31).…”

Histone deacetylase inhibitor Scriptaid reactivates latent HIV-1 promoter by inducing histone modification in in vitro latency cell lines

“…Margolis and colleagues demonstrated that the transcription factor YY1 can act as a repressor of HIV transcription by recruiting HDAC-1 to the provirus (11). Later studies demonstrated that nuclear factor (NF)-κB p50 homodimers (12), AP-4 (13), CTIP2 (14), Sp1 and c-Myc (15), and CBF-1 (16) can participate in HDAC-1 recruitment. HDAC-2 and -3 can also associate with the HIV long terminal repeat (LTR), and play a role in the repression of LTR expression (14,17).…”