Abstract
BackgroundThe major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny. Therefore, we evaluated the potential effects of THC on gamma herpesvirus replication.MethodsTissue cultures infected with various gamma herpesviruses were cultured in the presence of increasing concentrations of THC and the amount of viral DNA or infectious virus yield was compared to those of control cultures. The effect of THC on Kaposi's Sarcoma Associated Herpesvirus (KSHV) and Epstein-Barr virus (EBV) replication was measured by the Gardella method and replication of herpesvirus saimiri (HVS) of monkeys, murine gamma herpesvirus 68 (MHV 68), and herpes simplex type 1 (HSV-1) was measured by yield reduction assays. Inhibition of the immediate early ORF 50 gene promoter activity was measured by the dual luciferase method.ResultsMicromolar concentrations of THC inhibit KSHV and EBV reactivation in virus infected/immortalized B cells. THC also strongly inhibits lytic replication of MHV 68 and HVS in vitro. Importantly, concentrations of THC that inhibit virus replication of gamma herpesviruses have no effect on cell growth or HSV-1 replication, indicating selectivity. THC was shown to selectively inhibit the immediate early ORF 50 gene promoter of KSHV and MHV 68.ConclusionsTHC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesviruses, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication. The immediate early gene ORF 50 promoter activity was specifically inhibited by THC. These studies may also provide the foundation for the development of antiviral strategies utilizing non-psychoactive derivatives of THC.
Highlights
The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function
Virus, and THC The Kaposi's Sarcoma Associated Herpesvirus (KSHV) positive primary effusion lymphoma cell line BCBL-1 isolated by Don Ganem and co-workers [27], and BC-3 isolated by Ethel Cesarman and co-workers [28], were obtained through the US National Institutes of Health AIDS Research and Reference Reagent Program (Rockville, MD, USA) and from the American Type Culture Collection (Manassas, VA, USA)
THC inhibits KSHV and Epstein-Barr virus (EBV) DNA replication To evaluate the effect of THC on KSHV replication, we selected BCBL-1 and BC-3 lymphoblastoid cells because these cultures spontaneously produce small amounts of virus, and we used a previously published antiviral drug testing protocol [32] to determine whether THC induces or inhibits virus replication
Summary
The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function. Epstein-Barr virus (EBV) belongs to the same group of herpesviruses and is involved in human malignancies such as Burkitt's lymphoma, Hodgkin's disease, nasopharingeal carcinoma, and AIDS-associated lymphoma [for review, see [2]]. Related viruses such as herpesvirus saimiri (HVS) of monkeys and the murine gamma herpesvirus 68 (MHV-68) have been developed as animal models [3,4,5,6,7]. In response to extracellular signals, the latent virus can be reactivated leading to production of more infectious virus progeny This switch from latent to lytic infection is thought to be important in the pathogenesis of herpesviruses and the spread of infection within the organism and among individuals
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