Rapamycin Blocks Production of KSHV/HHV8: Insights into the Anti-Tumor Activity of an Immunosuppressant Drug

Abstract

BackgroundInfection with Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) often results in the development of fatal tumors in immunocompromised patients. Studies of renal transplant recipients show that use of the immunosuppressant drug rapamycin, an mTOR inhibitor, both prevents and can induce the regression of Kaposi's sarcoma (KS), an opportunistic tumor that arises within a subset of this infected population. In light of rapamycin's marked anti-KS activity, we tested whether the drug might directly inhibit the KSHV life cycle. We focused on the molecular switch that triggers this predominantly latent virus to enter the lytic (productive) replication phase, since earlier work links this transition to viral persistence and tumorigenesis.Methods and FindingsIn latently infected human B cell lines, we found that rapamycin inhibited entry of the virus into the lytic replication cycle, marked by a loss of expression of the lytic switch protein, replication and transcription activator (RTA). To test for viral-specific effects of rapamycin, we focused our studies on a B cell line with resistance to rapamycin-mediated growth inhibition. Using this line, we found that the drug had minimal effect on cell cycle profiles, cellular proliferation, or the expression of other cellular or latent viral proteins, indicating that the RTA suppression was not a result of global cellular dysregulation. Finally, treatment with rapamycin blocked the production of progeny virions.ConclusionsThese results indicate that mTOR plays a role in the regulation of RTA expression and, therefore, KSHV production, providing a potential molecular explanation for the marked clinical success of rapamycin in the treatment and prevention of post-transplant Kaposi's sarcoma. The striking inhibition of rapamycin on KSHV lytic replication, thus, helps explain the apparent paradox of an immunosuppressant drug suppressing the pathogenesis of an opportunistic viral infection.

Sirolimus and Secondary Skin-Cancer Prevention in Kidney Transplantation

“…33 Since the E6 oncoprotein activates the mTOR1 pathway, 34 we speculate that sirolimus might act on skin cancer through antiviral mechanisms that have been shown with other viruses, such as cytomegalovirus [35][36][37] and human herpesvirus 8. 38 In conclusion, in this study involving kidneytransplant recipients with at least one previous cutaneous squamous-cell carcinoma, conversion from calcineurin inhibitors to sirolimus was associated with a lower risk of subsequent skin cancers. The data suggest that the earlier the conversion occurs after an initial diagnosis of cutaneous squamous-cell carcinoma, the greater the efficacy.…”

Phosphorylation of Eukaryotic Translation Initiation Factor 4B (EIF4B) by Open Reading Frame 45/p90 Ribosomal S6 Kinase (ORF45/RSK) Signaling Axis Facilitates Protein Translation during Kaposi Sarcoma-associated Herpesvirus (KSHV) Lytic Replication

“…Rapamycin has proved very promising in treating KSHV-related diseases. It reduces KSHV-induced primary effusion lymphoma cell growth in culture and inhibits Kaposi sarcoma development in kidney transplant recipients (79,80), but some primary effusion lymphoma cell lines were found to be relatively resistant to rapamycin (79,81), and patient resistance to treatment has also been reported (82). The existence of a rapamycin-insensitive translational regulation mechanism suggests that combining an RSK inhibitor with rapamycin could be a successful strategy for the treatment of KSHV-related diseases (83).…”

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…Switching from cyclosporine A to rapamycin as the primary immunosuppressant has become the first line of therapy for transplant KS. The clinical phenotype can be recapitulated in preclinical models of KS and PEL (175)(176)(177)(178)(179). In KS, targeting mTOR was associated with a decrease in VEGF production.…”