Aspects of the present invention use gene expression profiling, and gene silencing methods to identify and provide a plurality of ‘validated’ KSHV-induced cellular gene sequences and pathways useful as targets for modulation of KSHV-mediated effects on cellular proliferation and phenotype (e.g., cancer) associated with latent and lytic phases of the Kaposi's sarcoma-associated herpesvirus (KSHV; Human herpesvirus 8; HHV8) life cycle. Particular embodiments provide therapeutic compositions, and methods for modulation and treatment of KSHV infection or KSHV-mediated effects on cellular proliferation and phenotype, comprising inhibition of KSHV-induced gene sequences or products thereof. Additional embodiments provide screening assays for compounds useful to modulate KSHV infection or KSHV-mediated effects on cellular proliferation and phenotype. Further embodiments provide diagnostic and/or prognostic assays for KSHV infection or related conditions. Additional embodiments provide novel in vivo models for KSHV infection or related conditions. Yet further aspects provide novel methods for transforming a mammalian cell, comprising expressing, by recombinant means, a transforming amount of RDCI, Neuritin, or both, and further provide cells transformed thereby.