Antri retrovial menk and atz

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Int. J. lmmunopharmac., Vol. 18, No. 5, pp. 305-309, 1996 Copyright Š 1996InternationalSocietyfor Immunopharmacology Publishedby ElsevierScienceLtd. Printedin Great Britain 0192~)561/96$15.00+ .00

Pergamon

PII: S0192--0561 (96)00033-1

A N T I - R E T R O V I R A L A C T I V I T Y OF M E T H I O N I N E E N K E P H A L I N A N D AZT IN A M U R I N E CELL C U L T U R E JOENG-IM SIN,* NICHOLAS PLOTNIKOFFt and STEVEN SPECTER*:~ *Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, 12901 N. Bruce B. Downs Blvd, Tampa, FL 33612, U.S.A. "~Department of Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, U.S.A. (Received 7 March 1996; revised 10 M a y 1996)

Abstract--Previously, this laboratory has demonstrated that azidothymidine used in combination with methionine enkephalin, an opioid pentapeptide, was more effectivethan AZT alone in inhibiting diseaseprogression due to murine retrovirus infections. In order to study the mechanism(s) by which Met-ENK mediates-antiviral effects, when used in combination with AZT in Friend leukemia virus infected mice, an in vitro focus forming assay was used. AZT at 1 ng/ml inhibited FLV replication by 30-50% in the susceptible Mus dunni cell line. By contrast, the immunostimulatory neuropeptide, Met-ENK, displayed no direct inhibition of viral replication. This suggests that Met-ENK does not have any direct anti-retroviral activity. Subsequent testing of Met-ENK in the presence of AZT showed no ability of this peptide to promote inhibition of viral replication due to AZT. By contrast, in the presence of mouse spleencells,as a source of lymphocytes,in vitro combination treatments using AZT and Met-ENK reduced FLV replication by 67%, compared to 47% using AZT alone. The inhibition due to Met-ENK was abrogated when spleen cells were pretreated with naloxone, an opioid antagonist. Therefore, we conclude that Met-ENK effects are mediated via opioid receptors on spleen cells and that the observed anti-FLV activity is dependent on the use of Met-ENK stimulated spleen cells in combination with AZT. Copyright Š 1996 International Society for Immunopharmacology Keywords: methionine enkepbalin, AZT, retrovirus, Friend leukemia virus.

The need for effective therapies for the human immunodeficiency virus (HIV) and other human retroviruses has led to the examination of both antiviral and immunomodulatory drugs. While 3'-azido-3'deoxythymidine (AZT) has been demonstrated to provide some benefit to HIV infected patients it has done little to prevent the progression of the acquired immunodeficiency syndrome (AIDS). Thus, newer approaches to therapy have sought to combine therapies for treatment of HIV infection and AIDS. In this regard murine retroviruses have been studied as AIDS models to evaluate the efficacy of therapy. Several studies have indicated that AZT could provide some protection against the murine retroviurus, Friend leukemia virus (FLV), and when combined with immunostimulants, including interleukin 2 and interferon, was more effective (Ciolli et al., 1991; Johnson et al., 1990; Morrey et al., 1990; Portnoi et al., 1990; Simard and Jolicoeur, 1991). Nevertheless, these approaches, using the same immunostimulantsas well as others, when applied to HIV infected individuals

have yet to demonstrate significant benefit (Johnson and Hirsch, 1990; Specter and Hadden, 1992). We have demonstrated more recently that the combination of an immunostimulatory neuropeptide, methionine enkephalin (Met-ENK), and AZT is more effective than either substance alone in reducing the morbidity and mortality due to the murine retroviruses FLV and the BM5 virus complex (Specter et al., 1994). This effect appeared to be the result of an antiviral effect of AZT and an immunostimulatory effect of Met-ENK, since AZT alone provided some protection while Met-ENK had no antiviral effect when used alone. Met-ENK has been shown to be an immunostimulator both in mice and humans, increasing CD4 lymphocyte counts in patients with AIDS or AIDS related complex (Wybran et al., 1987). Met-ENK has also been demonstrated to boost natural killer (NK) cell activity (Ghanta et al., 1991; Hsueh et al., 1992; Puente et al., 1992), cytokine levels and cytokine receptor expression (Marotti et al., 1994; Singh et al.,

~Author to whom correspondence should be addressed. 305


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