Abstract
Human immunodeficiency virus type 1 (HIV-1) persists in a latent state within resting CD4+ T cells of infected persons treated with highly active antiretroviral therapy (HAART). This reservoir must be eliminated for the clearance of infection. Using a cDNA library screen, we have identified methyl-CpG binding domain protein 2 (MBD2) as a regulator of HIV-1 latency. Two CpG islands flank the HIV-1 transcription start site and are methylated in latently infected Jurkat cells and primary CD4+ T cells. MBD2 and histone deacetylase 2 (HDAC2) are found at one of these CpG islands during latency. Inhibition of cytosine methylation with 5-aza-2′deoxycytidine (aza-CdR) abrogates recruitment of MBD2 and HDAC2. Furthermore, aza-CdR potently synergizes with the NF-κB activators prostratin or TNF-α to reactivate latent HIV-1. These observations confirm that cytosine methylation and MBD2 are epigenetic regulators of HIV-1 latency. Clearance of HIV-1 from infected persons may be enhanced by inclusion of DNA methylation inhibitors, such as aza-CdR, and NF-κB activators into current antiviral therapies.
Highlights
In human immunodeficiency virus (HIV)-infected individuals, highly active anti-retroviral therapy (HAART) dramatically reduces Human immunodeficiency virus type 1 (HIV-1) plasma titers [1,2,3] and decreases morbidity and mortality [4]
We demonstrate that one mechanism of latency is DNA methylation, in which chemical groups called methyl groups are added to HIV DNA
We identify a host protein called methyl-CpG binding domain protein 2 (MBD2) that binds methylated HIV DNA and is an important mediator of latency
Summary
In HIV-infected individuals, highly active anti-retroviral therapy (HAART) dramatically reduces HIV-1 plasma titers [1,2,3] and decreases morbidity and mortality [4]. Reactivation of latent HIV1, rendering it susceptible to HAART, is a critical component of any strategy for HIV-1 clearance [12,13,14]. In resting CD4+ T cells, HIV-1 is maintained in a latent state by multiple factors that inhibit virus gene expression after integration into cellular DNA. Sequence-specific transcription factors can recruit histone deacetylases (HDACs) and other chromatin-modifying enzymes to the provirus promoter, resulting in transcriptional repression and virus latency [15,16,17,18,19]. The provirus integration site can be a determinant of latency, either by making the provirus susceptible to transcriptional interference from cellular genes [21,22,23,24] or by suppressing virus transcription through the formation of heterochromatin [25]. Post-transcriptional mechanisms affecting the export [26] or translation [27] of HIV-1 mRNAs constitute other blocks to HIV-1 gene expression during latency
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