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)-α, -β, and -ρ-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, 2-5AN6B, to PBMC in culture. Addition of 2-5AN6B, but not zidovudine or saquinavir, to morphine-treated PBMC completely reversed the morphine-induced potentiation of HIV-1 infection. Further, 2-5AN6B significantly enhanced expression of both IFN-α and IFN-ρ. Also, increased expression of IFN-γ 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.
Address correspondence and reprint requests to Dr. Robert J. Suh adolnik, Department of Biochemistry, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. U.S.A.; e-mail:email@example.com
This work was supported by National Institutes of Health grants AI-34765 (R.J.S.), DA-14240 (R.J.S.), DA-11130 (T.J.R.), DA-06650 (T.J.R.). DA-14230 (T.J.R.), DA-12113 (E.E.H.), T32 DA-07237 (A.D.S.), T32 AI-07101 (A.D.S.), and P30 DA-13429 (T.J.R., E.E.H. and R.J.S.) and federal work study awards (J.W.H.).
The first two authors contributed equally to this work.
Manuscript received January 2, 2001; accepted February 26, 2002.
© 2002 Lippincott Williams & Wilkins, Inc.