CpG Methylation Controls Reactivation of HIV from Latency

PLoS Pathogens

Eric Verdin¹  Katerina Trejbalova¹  Ivan Hirsch¹  Jiri Hejnar⁴  Jana Blazkova⁴  Allan Guiguen⁴  Carine Van Lint⁵  Philippe Halfon⁵  Patrick Philibert⁶  Françoise Gondois-Rey⁷  Daniel Olive⁷ 

[1] and Institut Paoli-Calmettes, Marseille, France;Department of Infectious Diseases, Hôpital Ambroise Paré, Marseilles, France;Department of Virology, Alphabio Laboratory, Marseilles, France;Institut National de la Santé et de la Recherche Médicale (INSERM), UMR891, Centre de Recherche en Cancérologie de Marseille;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;Université Méditerranée, Marseille, France

关键词: DNA methylation;    HIV-1;    T cells;    Cloning;    Memory T cells;    Chromatin;    Polymerase chain reaction;    Viral replication;   

DOI  :  10.1371/journal.ppat.1000554

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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

【 授权许可】

CC BY