Epigenetic Regulation of HIV-1 Latency by Cytosine Methylation
Figure 7
Molecular mechanisms of HIV-1 latency: Role of cytosine methylation.
The first 821 nucleotides of the HIV-1 genome are shown, with genome position indicated relative to transcriptional start site. The virus promoter is comprised of the U3, R, and U5 regions. CpG island 2 is indicated by vertical lines, and filled circles on top of lines indicate methyl groups. Arrow indicates HIV-1 transcriptional start site. (A) Transcriptional repression during HIV-1 latency. Sequence-specific factors recruit HDAC1. CpG island 2 is methylated and bound by MBD2, which mediates transcriptional repression by recruitment of NuRD. (B) NF-κB activation triggers loss of p50 homodimers and CBF-1 from the HIV-1 promoter, resulting in decreased HDAC recruitment and partial reactivation of latent virus. Increased RelA (p65) recruitment has also been reported. Effects upon Yin-Yang 1 recruitment are unknown. (C) Treatment with aza-CdR decreases methylation of HIV-1 CpG islands, leading to a loss of MBD2 from the HIV-1 promoter. Latent virus is partially reactivated by removal of the methylation block. (D) Potent, synergistic reactivation of latent virus when NF-κB activation is combined with aza-CdR treatment. This occurs via loss of NF-κB-responsive transcriptional repressors and MBD2 from the HIV-1 promoter.