Chromatin-associated regulation of HIV-1 transcription: implications for the development of therapeutic strategies.
Human Immunodeficiency Virus type 1 (HIV-1) infection can now be treated effectively in many patients in the developed world, using combinations of antiretroviral therapeutics, called Highly Active Anti-Retroviral Therapy (HAART). However, despite prolonged treatment with HAART, the persistence of latently HIV-1-infected cellular reservoirs harboring transcriptionally silent but replication-competent proviruses represents the major hurdle to virus eradication. These latently infected cells are a permanent source for virus reactivation and lead to a rebound of the viral load after interruption of HAART. Therefore, a greater understanding of the molecular mechanisms regulating proviral latency and reactivation should lead to rational strategies aimed at purging these cellular reservoirs of HIV-1. This review summarizes our current knowledge and understanding of the elements involved in HIV-1 transcriptional reactivation: (1) the site of integration; (2) the transcription factor NF-kappaB, which is induced by proinflammatory cytokines (such as TNFalpha) and binds to two kappaB sites in the HIV-1 promoter region; (3) the specific remodeling of a single nucleosome (called nuc-1 and located immediately downstream of the HIV-1 transcription start site under latency conditions) upon activation of the HIV-1 promoter; (4) post-translational acetylation of histones and of non-histone proteins (following treatment with deacetylases inhibitors, which induce viral transcription and nuc-1 remodeling); and (5) the viral trans-activator Tat, which promotes transcription by mediating the recruitment to the HIV-1 promoter of histone-modifying enzymes and ATP-dependent chromatin remodeling complexes required for nucleosome disruption and transcriptional processivity. Finally, this review highlights experimental therapies aimed at administrating HIV-1 gene expression activators (such as HDAC inhibitors) combined with an effective HAART in order to reactivate and decrease/eliminate the pool of latently HIV-1-infected cellular reservoirs
Quivy
Vincent
V
University Libre de Bruxelles, Institut de Biologie et de Médecine Moléculaíres, Laboratoire de Virologie Moléculaire, 12, rue des Professeurs Jeener et Brachet 6041 Gosselies, Belgium.
De Walque
Stephane
S
Van Lint
Carine
C
D000107:Acetylation / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D003850:Deoxyribonuclease I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015696:Gene Products, tat / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009707:Nucleosomes / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016662:Virus Integration; D017735:Virus Latency; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D002843:Chromatin; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009707:Nucleosomes; D054322:tat Gene Products, Human Immunodeficiency Virus; D000255:Adenosine Triphosphate; D051548:Histone Acetyltransferases; D003850:Deoxyribonuclease I; D006655:Histone Deacetylases