| Autor: |
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 |
| Zdroj: |
AIDS Research & Human Retroviruses; Jan2007, Vol. 23 Issue 1, p123-134, 12p |
| Abstrakt: |
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 (2-5AN6B) that overcomes the HIV-1 induced blockades by restoring the 2-5OASRNase 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 2-5AN6Bon chronically infected CD4T lymphocytes and CD14monocytes derived from HIV-1-seropositive individuals. Wild-type HIV-1 replication was effectively inhibited by 2-5AN6Bin CD4T lymphocytes and CD14monocytes purified from HIV-1 seropositive individuals (n 18) compared to untreated cells. We also assessed the cytotoxicity of 2-5AN6Band report that 2-5AN6Bexerts its anti-HIV-1 activity with no evidence of cytotoxicity (IC90> 100,000 nM). Furthermore, 2-5AN6Bdid not alter the cellular RNA profile, affect CCR5 or CXCR4 coreceptor expression, or activate caspase-dependent apoptosis. Evidence is also provided to show that 2-5AN6B, and naturally occurring 2-5A4, act as ligands to activate human Toll-like receptor 4. These results indicate that the 2-5A agonist 2-5AN6Bhas the potential to enhance host cell innate and acquired immune defense mechanisms against HIV-1 infection. [ABSTRACT FROM AUTHOR] |
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