Hypoxia enhances the replication of oncolytic herpes simplex virus in p53- breast cancer cells

Abstract

Hypoxic cancer cells are refractory to conventional chemotherapy. Herpes simplex virus type-1 (HSV-1)-derived oncolytic viruses are safe for therapy since they lack the neurovirulence gene ICP34.5. Cancer cells containing high MEK activity are permissive to the HSV-1-derived oncolytic virus, R3616. Considering that hypoxia increases MEK activity, we determined whether hypoxic MDA-MB-231 and MCF-7 cells were more permissive to R3616, compared to normoxic cells. We observed nine-fold higher (3.5 x 10e6 pfu/ 4 x 10e5 pfu/ml) titers in MDA-MB-231 hypoxic cells compared to normoxic; however, hypoxic MCF-7 cells did not yield higher R3616 titers. Markers for early and late viral infection were consistent with this result:  1) virus-induced chaperone-enriched (VICE) domains were observed in MDA-MB-231 cells, and 2) the HSV-1 glycoprotein C (gC), a protein produced late in infection, accumulated in hypoxic MDA-MB-231 cells. Thus, oncolytic R3616 virus may target hypoxic p53- breast cancer cells.