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.
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Authors | Dessislava 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 |
Journal | AIDS research and human retroviruses
(AIDS Res Hum Retroviruses)
Vol. 23
Issue 1
Pg. 123-34
(Jan 2007)
ISSN: 0889-2229 [Print] United States |
PMID | 17263642
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- 2-5A(N6B)
- Adenine Nucleotides
- Anti-HIV Agents
- Immunologic Factors
- Lipopolysaccharide Receptors
- Oligoribonucleotides
- Toll-Like Receptor 4
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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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