title: Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR.
abstract: Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC, United States.
authors.forename: Geetaram
authors.initials: G
authors.lastname: Sahu
authors.affiliation: Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC, United States.
authors.forename: Kalamo
authors.initials: K
authors.lastname: Farley
authors.affiliation: Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.affiliation: Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC, United States.
authors.forename: Benjamas
authors.initials: B
authors.lastname: Aiamkitsumrit
authors.affiliation: Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Fassnacht
authors.affiliation: George Mason University, Manassas, VA, United States.
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
authors.affiliation: ICGEB, Wernher and Beit Building, Anzio Road, Observatory, 7925 Cape Town, South Africa.
authors.forename: Alex
authors.initials: A
authors.lastname: Ochem
authors.affiliation: Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC, United States.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Simon
authors.affiliation: Case Western Reserve University, Cleveland, OH, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Karn
authors.affiliation: Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC, United States; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037, United States. Electronic address: tmudit@email.gwu.edu.
authors.forename: Mudit
authors.initials: M
authors.lastname: Tyagi
mesh_terms: D002478:Cells, Cultured; D003042:Cocaine / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D009000:Monocytes / Q000187:drug effects / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D003042:Cocaine
keywords: Chromatin; Cocaine; Elongation; H3; HIV-1; MSK1; NF-ĸB; RSK1; Transcription; p65