title: 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.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Dessislava I
authors.initials: DI
authors.lastname: Dimitrova
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Reichenbach
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Pfleiderer
authors.forename: Ramamurthy
authors.initials: R
authors.lastname: Charubala
authors.forename: John P
authors.initials: JP
authors.lastname: Gaughan
authors.forename: Byungse
authors.initials: B
authors.lastname: Suh
authors.forename: Earl E
authors.initials: EE
authors.lastname: Henderson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Suhadolnik
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
mesh_terms: D000227:Adenine Nucleotides / Q000819:agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D006679:HIV Seropositivity; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D009843:Oligoribonucleotides / Q000819:agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C459131:2-5A(N6B); D000227:Adenine Nucleotides; D019380:Anti-HIV Agents; D007155:Immunologic Factors; D018950:Lipopolysaccharide Receptors; D009843:Oligoribonucleotides; D051197:Toll-Like Receptor 4