title: Inhibition of morphine-potentiated HIV-1 replication in peripheral blood mononuclear cells with the nuclease-resistant 2-5A agonist analog, 2-5A(N6B).
abstract: Opioids potentiate HIV-1 infection in vitro at least partly by suppressing immunoresponsive processes in human lymphocytes and monocytes. For example, it appears that morphine inhibits the interferon (IFN)-alpha, -beta, and -gamma-mediated natural antiviral defense pathways in human peripheral blood mononuclear cells (PBMC). In this study, we show that restoration of a key component of the antiviral pathway reverses morphine-potentiated HIV-1 infection of human PBMC. The data show that HIV-1 replication is potentiated and RNase L activity is inhibited after morphine administration. Because HIV-1 inhibits the antiviral pathway at the level of 2',5'-oligoadenylate (2-5A) synthetase and p68 kinase, antiviral enzymes that require double-stranded RNA, we overcame this blockade by the addition of the nuclease-resistant, nontoxic 2-5A agonist, 2-5A(N6B), to PBMC in culture. Addition of 2-5A(N6B), but not zidovudine or saquinavir, to morphine-treated PBMC completely reversed the morphine-induced potentiation of HIV-1 infection. Further, 2-5A(N6B) significantly enhanced expression of both IFN-alpha and IFN-gamma. Also, increased expression of IFN-gamma was associated with a significant increase in expression of RANTES and monocyte chemotactic protein (MCP)-1, chemokines that may inhibit HIV-1 infection by blocking viral attachment to CCR2 and CCR5 co-receptors. Our results suggest that reactivation of the antiviral pathway by 2-5A agonists may be useful to inhibit opioid-potentiated HIV-1 replication.
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Homan
authors.forename: Amber D
authors.initials: AD
authors.lastname: Steele
authors.forename: Camille
authors.initials: C
authors.lastname: Martinand-Mari
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
authors.forename: Earl E
authors.initials: EE
authors.lastname: Henderson
authors.forename: Ramamurthy
authors.initials: R
authors.lastname: Charubala
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Pfleiderer
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Reichenbach
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Suhadolnik
mesh_terms: D000227:Adenine Nucleotides / Q000819:agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000032:analysis / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000032:analysis / Q000096:biosynthesis; D004722:Endoribonucleases / Q000096:biosynthesis / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000032:analysis / Q000096:biosynthesis; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology*; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000819:agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000819:agonists; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
chemical_list: C459131:2-5A(N6B); D000227:Adenine Nucleotides; D000998:Antiviral Agents; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D017320:HIV Protease Inhibitors; D016898:Interferon-alpha; D009294:Narcotics; D009843:Oligoribonucleotides; D011500:Protein Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; C023505:2',5'-oligoadenylate; D009020:Morphine; D007371:Interferon-gamma; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D019258:Saquinavir