Skip to main content


  • Oral presentation
  • Open Access

CpG methylation controls reactivation of HIV from latency

  • 1, 2, 3,
  • 1, 2,
  • 1,
  • 4,
  • 5,
  • 6,
  • 1,
  • 3,
  • 2 and
  • 1Email author
Retrovirology20107 (Suppl 1) :O8

  • Published:


  • Long Terminal Repeat
  • Hydroxamic Acid
  • Latent Reservoir
  • Jurkat Cell Line
  • Transcriptional Interference


DNA methylation of retroviral promoter and enhancer 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.


We analyzed the relation of latent and reactivated HIV-1 promoters in a model of Jurkat cell lines and in memory CD4+ T cells of long-term aviremic patients by means of bisulfit sequencing and chromatin immunoprecipitation in cell-sorted populations. To assess the resistance of latent HIV-1 to reactivation we exposed the cells to TNF-α, protein kinase C agonists, inhibitors of HDAC, and inhibitors of DNA methyltransferases.


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. 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-α, 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.


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. Tight but incomplete control of HIV-1 latency by CpG methylation might have important implications for strategies aimed at eradicating HIV-1 infection.

Authors’ Affiliations

INSERM, UMR891, Centre de Recherche en Cancérologie de Marseille and Institut Paoli-Calmettes, and Université Méditerranée, Marseille, France
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
Laboratory of Molecular Virology, Institute for Molecular Biology and Medicine (IBMM) University of Brussels (ULB), Gosselies, Belgium
Department of Virology, Alphabio Laboratory, Marseille, France
Department of Infectious Diseases, Hôpital Ambroise Paré, Marseille, France
Gladstone Institute of Virology and Immunology, San Francisco, USA


© Blazkova et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.