CpG methylation controls reactivation of HIV from latency

PLoS Pathog. 2009 Aug;5(8):e1000554. doi: 10.1371/journal.ppat.1000554. Epub 2009 Aug 21.

Abstract

DNA methylation of retroviral promoters and enhancers localized in the provirus 5' long terminal repeat (LTR) is considered to be a mechanism of transcriptional suppression that allows retroviruses to evade host immune responses and antiretroviral drugs. However, the role of DNA methylation in the control of HIV-1 latency has never been unambiguously demonstrated, in contrast to the apparent importance of transcriptional interference and chromatin structure, and has never been studied in HIV-1-infected patients. Here, we show in an in vitro model of reactivable latency and in a latent reservoir of HIV-1-infected patients that CpG methylation of the HIV-1 5' LTR is an additional epigenetic restriction mechanism, which controls resistance of latent HIV-1 to reactivation signals and thus determines the stability of the HIV-1 latency. CpG methylation acts as a late event during establishment of HIV-1 latency and is not required for the initial provirus silencing. Indeed, the latent reservoir of some aviremic patients contained high proportions of the non-methylated 5' LTR. The latency controlled solely by transcriptional interference and by chromatin-dependent mechanisms in the absence of significant promoter DNA methylation tends to be leaky and easily reactivable. In the latent reservoir of HIV-1-infected individuals without detectable plasma viremia, we found HIV-1 promoters and enhancers to be hypermethylated and resistant to reactivation, as opposed to the hypomethylated 5' LTR in viremic patients. However, even dense methylation of the HIV-1 5'LTR did not confer complete resistance to reactivation of latent HIV-1 with some histone deacetylase inhibitors, protein kinase C agonists, TNF-alpha, and their combinations with 5-aza-2deoxycytidine: the densely methylated HIV-1 promoter was most efficiently reactivated in virtual absence of T cell activation by suberoylanilide hydroxamic acid. Tight but incomplete control of HIV-1 latency by CpG methylation might have important implications for strategies aimed at eradicating HIV-1 infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • CD4-Positive T-Lymphocytes / metabolism
  • Chromatin / physiology
  • Clone Cells
  • Cloning, Molecular
  • CpG Islands*
  • DNA Methylation*
  • Female
  • HIV Infections / metabolism
  • HIV Long Terminal Repeat
  • HIV Seronegativity
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Humans
  • Jurkat Cells
  • Male
  • Middle Aged
  • Promoter Regions, Genetic
  • Proviruses / genetics
  • Proviruses / metabolism
  • Viremia / genetics
  • Viremia / metabolism
  • Virus Latency / physiology*

Substances

  • Chromatin