KSHV: forgotten but not gone.

S ince then, almost no progress has been made in treating the virus that causes these tumors. In this issue of Blood, for the first time, Uldrick et al describe a long overdue approach to MCD therapy based on direct targeting of KSHV.4 There are now 7 known human cancer viruses but only scattered efforts to developed drugs specifically targeting them. The successes of the human papillomavirus and hepatitis B virus vaccines make clear that virusoriented therapies have the potential to be major success stories in cancer management. If a virus causes a tumor, why are most pharmaceuticals targeting the host cancer cell instead of the causative virus? The most important reason is economics: 1 in 5 cancers worldwide has an infectious origin, with most cases concentrated in poor and developing countries. But to be fair to the pharmaceutical industry, drugs against viral cancers are also difficult to make. Almost all current antivirals target viral replication machinery. The most wellknown antiviral drug is acyclovir, a nucleoside analog activated by the herpes simplex thymidine kinase enzyme. This viral protein is only expressed during active viral replication to replicate viral DNA and for this reason acyclovir is effective against cold sores but not against latent virus in trigeminal or sacral ganglia. Acyclovir reduces symptoms but does not cure the underlying disease. Similarly, viruses in most tumor cells are latent as well. If viruses in cancer cells did actively replicate, host innate and adaptive immune responses would kill the cell before it could grow into a clinically apparent tumor, and for most viral cancers there is no target that can be hit with available drugs. Ganciclovir, for example, is remarkably effective in randomized clinical trials to prevent KSHV replication and KS5,6 but has no effect once KS tumors emerge.7 The study by Uldrick et al looks at this problem in a different way—are there any other KSHV-related tumors in which actively replicating virus can be targeted? Castleman disease is a B-cell lymphoproliferative disorder driven by IL-6 over-expression and in KSHV-related MCD, only a small percentage of tumor cells are actually KSHV-infected (see figure). KSHV-infected MCD cells are surrounded by uninfected B cells forced to multiply by cytokine-induced mitogenesis, which make up the bulk of MCD tumors and are responsible for most MCD symptoms and sequelae. Viral replication machinery plays a key role in MCD because KSHV-encoded vIL-6 is amplified as part of the virus’s replication program (although the KSHV vIL-6 gene can be activated in different ways and should not be called a “lytic KSHV gene”). KSHV-infected cells expressing vIL-6 within an adventitious germinal center in a multicentric Castleman disease tumor. Illustration courtesy of C. Parravicini.