The molecular basis of lytic induction therapy in relation to gamma herpesvirus (KSHV, EBV)-associated, AIDS-related tumors

Abstract

The frequent presence of the EBV and KSHV genomes in AIDS-related lymphomas has suggested that manipulation of EBV and/or KSHV viral gene expression in these tumors might be used to promote tumor cell death, while sparing uninfected normal cells. Although EBV and KSHV can infect B cells for the life of the host, following recovery from primary infection, very few normal B cells are infected (usually fewer than one in a million B cells in the case of EBV-infected individuals) (Babcock et al., 2001, Methods Mol Biol 174, 103-110; Hochberg and Thorley-Lawson, 2005, Methods Mol Biol 292, 39-56). In contrast, essentially all of the tumor cells of EBV-and/or KSHV-associated malignancies contain the virus. Thus, the development of therapies that can induce killing of all EBV-infected cells in the body would be expected to dramatically reduce tumor cell viability, while potentially having no effect on healthy cells. One of the most promising approaches for inducing specific killing of EBV-infected host cells is commonly referred to as lytic induction therapy (Gutiérrez et al., 1996, Cancer Res 56, 969-972; Westphal et al., 1999, Cancer Res 59, 1485-1491; Israel and Kenney, 2003, Oncogene 22, 5122-5130). As the name implies, the goal of this approach is to convert the latent type of EBV infection that normally occurs in tumor cells into the lytic form of viral infection, thereby using the virus itself to kill tumor cells. Although this type of approach is potentially applicable for both EBV-associated and KSHV-associated malignancies, the development of EBV-directed lytic induction therapies is further advanced and thus will be the primary focus of most of the discussion herein. © 2010 Springer Science+Business Media, LLC.