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Inhibition of HIV type 1 replication in CD4+ and CD14+ cells purified from HIV type 1-infected individuals by the 2-5A agonist immunomodulator, 2-5A(N6B).

Abstract
Two major interferon (IFN)-mediated antiviral defense enzymes are double-stranded (ds)RNA-dependent 2',5'-oligoadenylate (2-5A) synthetase (2-5OAS) and p68 kinase (PKR). When activated by dsRNA, 2-5OAS synthesizes 2-5A, which binds to and activates RNase L. Activated RNase L hydrolyzes single-stranded viral RNA, thereby inhibiting viral protein synthesis. HIV-1 inhibits the IFN-mediated intracellular antiviral pathways. We have reported the synthesis and characterization of a nuclease-resistant 2-5A agonist (2-5A(N6B)) that overcomes the HIV-1 induced blockades by restoring the 2-5OAS/RNase L antiviral pathway (Homan JW, et al., J Acquir Immune Defic Syndr 2002;30:9-20). The objective of this study was to test the effect of 2-5A(N6B) on chronically infected CD4(+) T lymphocytes and CD14(+) monocytes derived from HIV-1-seropositive individuals. Wild-type HIV-1 replication was effectively inhibited by 2-5A(N6B) in CD4(+) T lymphocytes and CD14(+) monocytes purified from HIV-1 seropositive individuals (n = 18) compared to untreated cells. We also assessed the cytotoxicity of 2-5A(N6B) and report that 2-5A(N6B) exerts its anti-HIV-1 activity with no evidence of cytotoxicity (IC(90) > 100,000 nM). Furthermore, 2-5A(N6B) did not alter the cellular RNA profile, affect CCR5 or CXCR4 coreceptor expression, or activate caspase-dependent apoptosis. Evidence is also provided to show that 2-5A(N6B), and naturally occurring 2-5A(4), act as ligands to activate human Toll-like receptor 4. These results indicate that the 2-5A agonist 2-5A(N6B) has the potential to enhance host cell innate and acquired immune defense mechanisms against HIV-1 infection.
AuthorsDessislava I Dimitrova, Nancy L Reichenbach, Xiaowei Yang, Wolfgang Pfleiderer, Ramamurthy Charubala, John P Gaughan, Byungse Suh, Earl E Henderson, Robert J Suhadolnik, Thomas J Rogers
JournalAIDS research and human retroviruses (AIDS Res Hum Retroviruses) Vol. 23 Issue 1 Pg. 123-34 (Jan 2007) ISSN: 0889-2229 [Print] United States
PMID17263642 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 2-5A(N6B)
  • Adenine Nucleotides
  • Anti-HIV Agents
  • Immunologic Factors
  • Lipopolysaccharide Receptors
  • Oligoribonucleotides
  • Toll-Like Receptor 4
Topics
  • Adenine Nucleotides (agonists, chemical synthesis, pharmacology)
  • Adult
  • Aged
  • Anti-HIV Agents (pharmacology)
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes (drug effects, virology)
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Female
  • Flow Cytometry
  • HIV Infections (drug therapy, metabolism)
  • HIV Seropositivity
  • HIV-1 (drug effects, physiology)
  • Humans
  • Immunologic Factors (pharmacology)
  • Lipopolysaccharide Receptors
  • Male
  • Middle Aged
  • Monocytes (cytology, immunology)
  • Oligoribonucleotides (agonists, chemical synthesis, pharmacology)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 4 (metabolism)
  • Virus Replication (drug effects)

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