Here's a selection from the THC-antiviral paper itself, for those interested in a more in-depth look:
Delta-9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro [2004]
Maria M Medveczky, Tracy A Sherwood, Thomas W Klein, Herman Friedman and Peter G Medveczky
Department of Medical Microbiology and Immunology, MDC Box 10, University of South Florida, and the H. Lee Moffitt Cancer Center, 12901 Bruce B. Downs Blvd, Tampa, FL 33612-4799, USA
BMC Medicine 2004, 2:34doi:10.1186/1741-7015-2-34
The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1741-7015/2/34
Background
Reactivation of latent virus is often initiated by extracellular signals activating through receptors and various transcription factors. Transcription factors activate the promoter of the critical viral gene open reading frame 50 (ORF 50) of KSHV, HVS, MHV 68 or its homologue Rta of EBV [8-16]. The ORF 50 protein is also a transcription factor and further boosts production of its own mRNA [10,13,16]. An important function of ORF50/Rta is to activate early lytic genes [1,2] involved in DNA synthesis. After synthesis of early proteins, the process culminates with expression of late genes leading to production of virion components, virus assembly, release of progeny virus and cell death.
The major psychoactive cannabinoid compound of marijuana, ?9 tetrahydrocannabinol (THC), has been shown to modulate and primarily suppress immune responses against various pathogens [for review see [17,18]]. THC binds to and activates either one of the two cannabinoid receptors (CB1 and CB2) located on the surface of both brain and lymphoid cells [17-26]. CB1 and CB2 belong to the family of G protein-coupled receptors characterized by seven transmembrane loops interacting with the ligand on the outer surface of the cell. The receptors also contain an intracellular signaling domain.
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Since THC is an immune modulator we hypothesized that it may have an effect on gamma herpesvirus replication and/or latency.
The data presented show that THC inhibits reactivation and lytic replication of these herpesviruses, possibly through inhibition of the ORF 50 promoter.
Discussion
To summarize the antiviral effects of THC and to compare THC with well-characterized antiviral drugs, we compiled data from the literature as well as from our own experimental results. Table 2 shows the 50% inhibitory concentrations (IC50) of four known antiviral drugs and of THC. Data on the antiviral effects of acyclovir, PFA and ganciclovir on KSHV were obtained from our Gardella gel assays [32]. Usherwood et al. [33] also used a Gardella gel-based assay to determine the effect of acyclovir against MHV 68 in transformed B cell line S11. The data regarding the effects of four antiviral drugs against MHV 68 and on cell division are from the work of Neyts and De Clercq [34] using standard lytic virus replication inhibition assays on monolayers. The THC antiviral results are from the data described in this paper (Gardella gels for KSHV using BCBL-1 cells and NIH12 antiviral assays for MHV 68). These data suggest that THC is a potent and selective antiviral agent against KSHV comparable with some well-characterized anti-herpesvirus compounds. THC is even more potent and selective against MHV 68 than acyclovir, ganciclovir and foscarnet. Cidofovir appears to be most potent in these in vitro experiments; however, this drug is known to cause serious side effects and is toxic to the kidney in humans.
As outlined earlier, THC can modulate and inhibit the activation of immune cells, so it is not entirely surprising that it can down-regulate the reactivation of viruses residing in lymphocytes, as shown by the data. However, the antiviral effect of THC is not cell specific, since MHV 68 and HVS replication was also strongly inhibited by THC in NIH3T12 or owl monkey kidney monolayer cell cultures.
This observation suggests that THC either directly or indirectly targets a viral gene shared by these herpesviruses.
The data presented in Figure 7 suggest that THC may inhibit KSHV replication through the cannabinoid receptors. When BCBL-1 cells were treated with THC the receptor antagonists partially reversed this effect, suggesting a role for the CB receptors expressed by BCBL-1 cells. However, more studies are required to evaluate whether CB1, CB2 or both receptors are involved. As discussed in the Introduction, ORF 50/Rta is a critical gene for both reactivation of latent virus and lytic replication in monolayers. Interestingly, ORF 50/Rta activation involves cAMP signaling [12,35]. In contrast, cannabinoid receptor binding has been shown to down-regulate the level of activated CREB through a decrease in cyclic AMP synthesis [17,18,26,36]. Therefore, one possible explanation is that THC inhibits cAMP signaling, leading to decrease of ORF 50/Rta-mediated transcription and block of virus replication. This antiviral mechanism of THC is supported by our data. Luciferase reporter assays showed that in the presence of THC, initiation of transcription of ORF 50 mRNA in both KSHV and MHV 68 is markedly reduced (4-fold and 7.4-fold, respectively) as compared with the CMV immediate early promoter. These data suggest selective inhibition of the ORF 50 promoter of MHV 68 and KSHV by THC.
However, it is also anticipated that THC may also block other cellular and viral genes, as this drug has been shown to cause a wide range of changes in lymphocyte gene expression [17,18].
Conclusions
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Interestingly, statistical analysis indicates a lower incidence of Kaposi's sarcoma in HIV positive women using non-intravenous drugs [45]. About 5.4% of HIV positive women with no drug use developed KS, whereas none of the 47 women in this study who only used marijuana suffered from KS [ref. [45], and James Goedert, personal communication]. This report, however, involved relatively few individuals so further analysis of a larger cohort is warranted.
We believe that studies on cannabinoids and herpesviruses are important to continue because there are obvious potential benefits. Better understanding may lead to the development of specific non-psychoactive drugs that may inhibit reactivation of oncogenic herpesviruses.
