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.
Highlights
The tumorigenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV, human herpesvirus 8 or HHV8) is the causative agent of primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD), and, most commonly, Kaposi’s sarcoma (KS) [1,2]
These results indicate that mammalian target of rapamycin (mTOR) plays a role in the regulation of Replication and transcription activator (RTA) expression and, 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, helps explain the apparent paradox of an immunosuppressant drug suppressing the pathogenesis of an opportunistic viral infection
Summary
The tumorigenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV, human herpesvirus 8 or HHV8) is the causative agent of primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD), and, most commonly, Kaposi’s sarcoma (KS) [1,2]. KSHV, as with all herpesviruses, has both a latent phase in which the virus expresses few proteins, as well as a lytic phase during which virion production occurs. KSHV reactivates in the presence of phorbol esters, such as 2-O-tetradecanoyl-phorbol-13-acetate (TPA), that upregulate the Raf/MEK/ERK pathway [9] and cobalt chloride, a hypoxia mimetic, that elevates levels of hypoxia inducible factor-1 alpha (HIF-1a) [10,11]. While these three induction pathways result in increased RTA expression, it is unclear whether these signaling pathways are independent or, instead, share regulatory control points upstream of RTA. 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
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