skip to main content

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

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. - Highlights: • Cocaine induces the initiation phase of HIV transcription by activating NF-ĸB. • Cocaine induced NF-ĸB phosphorylation promotes its interaction with P300. • Cocaine enhances the elongation phase of HIV transcription by stimulating MSK1. • Cocaine activated MSK1 catalyzes the phosphorylation of histone H3 at its Ser10. • Cocaine inducedmore » H3S10 phosphorylation facilitates the recruitment of P-TEFb at LTR.« less
Authors:
;  [1] ;  [2] ; ;  [1] ;  [3] ;  [4] ;  [1] ;  [5] ;  [2] ;  [1] ;  [6]
  1. Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC (United States)
  2. Virginia Commonwealth University, Richmond, VA (United States)
  3. George Mason University, Manassas, VA (United States)
  4. ICGEB, Wernher and Beit Building, Anzio Road, Observatory, 7925 Cape Town (South Africa)
  5. Case Western Reserve University, Cleveland, OH (United States)
  6. (United States)
Publication Date:
OSTI Identifier:
22470187
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 483; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS VIRUS; CENTRAL NERVOUS SYSTEM; CHROMATIN; COCAINE; GENES; HUMAN POPULATIONS; INTERACTIONS; MACROPHAGES; MODIFICATIONS; MONOCYTES; PHOSPHORYLATION; SERINE; SIGNALS; STRESSES; TRANSCRIPTION