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How KSHV Evades the Immune Response

marta gaglia and tate tabtieng and their research

Marta Gaglia & Tate Tabtieng with a diagram of IFN signalling during KSHV infection

Nearly 15% of all human cancers are caused by oncogenic viruses. One such virus is Kaposi’s sarcoma-associated herpesvirus (KSHV), the cause of Kaposi’s sarcoma, a common AIDS-associated malignancy that is also one of the leading causes of cancer in sub-Saharan Africa. In the US, Kaposi’s sarcoma is a growing concern for organ transplant recipients and affects 1 in 200 of these patients. Currently, Kaposi’s sarcoma remains poorly treatable, and no effective drugs exist that directly target KSHV infection.

An essential component of successful viral infection is the ability of viruses to evade early innate immune responses. This feature could be exploited for therapeutic interventions aimed at boosting our body’s responses to KSHV and other viruses. A key player in early innate immune responses are type I interferons (IFNs), potent anti-viral secreted cellular factors that are quickly induced after viral infection and orchestrate downstream signaling that inhibits viral replication and prevents the spread of infection. Our understanding of how KSHV evades these early innate immune responses remains incomplete.

Tate Tabtieng, a PhD student in the Biochemistry program in Marta Gaglia’s lab, is studying how KSHV subverts type I IFN signaling to establish a productive infection. He has observed that KSHV replication triggers minimal type I IFN signaling, suggesting that the virus is able to efficiently block IFN induction. In collaboration with the lab of Alexei Degterev, who has expertise in cell death pathways, Tate has shown that KSHV exploits the activity of caspases, cellular enzymes that regulate cell death and inflammation, to suppress type I IFN signaling. First, inhibition of caspases with the pan-caspase inhibitor, IDN-6556, resulted in a strong induction of type I IFN signaling in KSHV-infected cells. Moreover, caspase inhibition was able to reduce KSHV replication. Importantly, Tate showed that the block in viral replication was directly due to increased IFN signaling, since replication in the presence of caspase inhibitors was restored when the type I interferon IFN-β was reduced using siRNA knock down. These findings raise the possibility that caspases could be novel therapeutic targets for Kaposi’s sarcoma and other KSHV-associated diseases. This is particularly interesting because small molecules that inhibit caspase activity are already being developed for other applications and could be repurposed for KSHV treatment.

Tate’s current work focuses on finding out how caspases suppress type I IFN signaling. Beside their function in response to infection, type I IFNs play important roles in many other diseases. For example, type I IFNs potentiate tumor immunity. Also, their dysregulation contributes to many autoimmune and inflammatory diseases. In addition to Tate’s work, other studies have linked caspases to the attenuation of innate immune responses, suggesting this regulatory mechanism is not unique to KSHV infection. Thus, the Gaglia lab’s studies on caspase-dependent regulation of type I IFN signaling will have implications for a wide-range of applications in human physiology and disease, and for therapies that target the type I IFN system.

Tabtieng T, Degterev A, Gaglia MM. 2018. Caspase-Dependent Suppression of Type I Interferon Signaling Promotes Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. J Virol. 92: e00078-18. Abstract

Tabtieng T, Gaglia MM. 2018. Emerging pro-viral roles of caspases during lytic replication of gammaherpesviruses. J Virol Epub ahead of print. Abstract

This research was supported by a grant from the American Cancer Society.