Delta (9)-Tetrahydrocannabinol Contributes to the Development of Kaposi’s Sarcoma.

Kaposi’s sarcoma-associated herpesvirus (KSHV), a DNA tumor virus, appears to be necessary but not sufficient for the development of Kaposi’s sarcoma (KS). This is highlighted by the observation that most KSHV infections are asymptomatic, and more than 95% of persons who become infected never develop KS or other KSHV-related cancers. In addition to KSHV, a variety of factors, including HIV-1 Tat protein, may contribute to the pathogenesis of KS. These cofactors usually induce immunosuppression, enhance susceptibility to infection, modulate the viral life cycle, and/or stimulate angiogenesis and tumorigenesis either individually or in combination.

Delta (9)-Tetrahydrocannabinol (THC), the major active component of marijuana, has been prescribed for medicinal use and has also been reported to induce immunosuppression. To date, contradictory observations have been made about its effects on viral infection/replication and on tumor cell growth. This prompted us to study the biological effect of Δ⁹-THC on KSHV, and obtain more evidence to assess the potential risks versus benefits of THC administration among KSHV-positive populations. We found an increased efficiency of KSHV infection (40% vs 15%) in human dermal microvascular endothelial cells (HMVEC) in the presence of low concentrations of Δ⁹-THC (10–100 nM). THC enhanced endocytosis and cell-cell adhesion by 30–60%, which may account for this increase in infection efficiency. Using real-time DNA PCR technology, the number of copies of the KSHV latent gene, LANA-1, was quantitated and correlated with the viral load in endothelial cells. We found that Δ⁹-THC increased the viral load 20–100 fold in KSHV-infected endothelial cells as compared to treatment with the vehicle control. We then quantitated expression of the KSHV lytic switch gene ORF50 (RTA) by real-time RT-PCR, in the presence or absence of Δ⁹-THC. ORF50 expression was shown to be up-regulated by Δ⁹-THC, leading to increased KSHV loads. We also observed that comparable concentrations of Δ⁹-THC up-regulated vGPCR expression, thereby fostering endothelial transformation and inducing significantly more colony-formation (1.5 fold) in soft agar. Our results indicate that Δ⁹-THC may enhance KSHV infection, transmission, replication, and viral-mediated endothelial transformation. Thus, THC administration may put individuals at greater risk for the development and growth of Kaposi’s sarcoma.