Mitochondria as functional targets of proteins coded by human tumor viruses

Molecular analyses of tumor virus-host cell interactions have provided key insights into the genes and pathways involved in neoplastic transformation. Recent studies have revealed that the human tumor viruses Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human T-cell leukemia virus type 1 (HTLV-1) express proteins that are targeted to mitochondria. The list of these viral proteins includes BCL-2 homologues (BHRF1 of EBV; KSBCL-2 of KSHV), an inhibitor of apoptosis (IAP) resembling Survivin (KSHV K7), proteins that alter mitochondrial ion permeability and/or membrane potential (HBV HBx, HPV E1^4, HCV p7, and HTLV-1 p13^II), and K15 of KSHV, a protein with undefined function. Consistent with the central role of mitochondria in energy production, cell death, calcium homeostasis, and redox balance, experimental evidence indicates that these proteins have profound effects on host cell physiology. In particular, the viral BCL-2 homologues BHRF1 and KSBCL-2 inhibit apoptosis triggered by a variety of stimuli. HBx, p7, E1^4, and p13^II exert powerful effects on mitochondria either directly due to their channel-forming activity or indirectly through interactions with endogenous channels. Further investigation of these proteins and their interactions with mitochondria will provide important insights into the mechanisms of viral replication and tumorigenesis and could aid in the discovery of new targets for anti-tumor therapy.