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JAIDS Journal of Acquired Immune Deficiency Syndromes:
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Inhibition of Morphine-Potentiated HIV-1 Replication in Peripheral Blood Mononuclear Cells With the Nuclease-Resistant 2-5A Agonist Analog, 2-5AN6B.

Homan, Joseph W.; Steele, Amber D.; Martinand-Mari, Camille; Rogers, Thomas J.; Henderson, Earl E.; Charubala, Ramamurthy; Pfleiderer, Wolfgang; Reichenbach, Nancy L.; Suhadolnik, Robert J.

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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 -[rho]-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-[alpha] and IFN-[rho]. 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.

(C) 2002 Lippincott Williams & Wilkins, Inc.

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