RESUMO
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-kappaB activators prostratin or TNF-alpha 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-kappaB activators into current antiviral therapies.
Assuntos
Citosina/metabolismo , Metilação de DNA , Epigênese Genética , HIV-1/fisiologia , Latência Viral/genética , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Ilhas de CpG , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Decitabina , HIV-1/genética , Humanos , Células Jurkat , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Proteínas Repressoras/metabolismo , TransfecçãoRESUMO
Wastewater treatment sludge contains valuable nutrients, yet represents a residue problem due to the amount of heavy metals, which is one of the factors preventing the use of sludge as fertilizer. In Sweden, the government has a declared aim of closing the ecocycles of nutrients to arable land, while at the same time the existing limit values are among the lowest in the world. This paper focuses on the opportunities for Swedish wastewater utilities (WWUs) to manage and reduce sources of heavy metals in order to get sludge approved and recycled. A case study focusing on sources of the heavy metals Cd, Cu, Hg, Ni, Pb, and Zn and the WWUs ability to influence the source by means of existing regulations was traced and categorized. A substantial fraction of the heavy metals were shown to be caused by diffuse emissions, such as the use of goods and products in society. For most sources discussed in the paper, a WWU can only manage the sources to a limited extent, if at all. This study shows that the WWUs cannot manage both recycling of nutrients and a decrease in heavy metals ending up in sludge. Diffuse emissions of heavy metals must be examined in context, not as a separate phenomenon or an issue for a single actor. The existing environmental legislation does not handle diffuse sources, yet long-term strategies for reducing the emissions to wastewater treatment must involve the reduction of diffuse emissions.
