Subversion of autophagy by Kaposi's sarcoma-associated herpesvirus impairs oncogene-induced senescence

Approximately fifteen percent of all human cancers are caused by viral infection. In people suffering from AIDS, co-infection with the Kaposi's sarcoma- associated herpesvirus (KSHV, human herpesvirus-8) causes a tumour known as Kaposi's sarcoma (KS). It is not known precisely how KSHV causes tumour formation, but the emerging model is that different viral gene products cooperate to reprogram host cells and undermine host anti-viral and anti- cancer defences. My work in the McCormick laboratory has uncovered a novel mechanism by which KSHV undermines host pathways to promote the uncontrolled proliferation characteristic of cancer cells. I have identified two KSHV proteins, v-cyclin and v-FLIP, that carryout a coordinated attack on host proliferation pathways. During KSHV infection v-cyclin drives accelerated growth and division of host cells, whereas v-FLIP disables intrinsic cellular 'brakes' that typically prevent uncontrolled proliferation. Remarkably, v-FLIP disables host anti-proliferative mechanisms by interfering with autophagy, the process of cellular recycling. v-FLIP inhibition of autophagy helps KSHV avoid being recycled and prevents host cells from recycling parts of themselves to generate raw materials for the synthesis of anti-viral and anti-cancer defence proteins. Importantly, I have also observed that treatment of KSHV-infected cells with drugs that strongly induce cellular recycling, such as rapamycin, restores the anti-proliferative 'brakes' of host cells and helps explain the effectiveness rapamycin in the treatment of KS. Together, this work demonstrates that KSHV promotes the uncontrolled proliferation characteristic of cancer cells by simultaneously stimulating host cell growth and division, and blocking autophagy. Viruses are excellent teachers, and study of KSHV is likely to provide novel insights into the mechanisms that contribute to tumourigenesis and highlight pathways that may be targeted to treat specific forms of cancer.