The human cytomegalovirus vMIA protein inhibits apoptosis and innate immune signaling in human Mueller cells.

Human cytomegalovirus (HCMV) encodes the viral mitochondria-localized inhibitor of apoptosis (vMIA) protein which blocks host cell apoptosis. vMIA also inhibits innate immune signaling through the DNA sensing cGAS-STING pathway and the RNA sensing RLR pathway which interacts with the mitochondrial adapter protein MAVS. We demonstrate stable expression and mitochondrial localization of vMIA in a human Mueller cell line (MIO-M1). In a real time apoptosis assay, vMIA significantly reduced staurosporine (STS)-induced apoptosis in MIO-M1 cells. In addition, immunoblots indicated that vMIA blocked apoptotic cleavage of the nuclear enzyme PARP1. vMIA also reduced STS mediated necrosis at later time points in MIO-M1 cells. The steady state level of cGAS protein was increased in vMIA expressing MIO-M1 cells. In contrast, vMIA decreased the amount of STING protein in MIO-M1 cells. A decrease in the percentage of aggregated mitochondrial antiviral-signaling protein (MAVS), and alteration of the classic mitochondrial localization of MAVS, in the presence of vMIA suggested that vMIA induced changes in mitochondrial morphology in MIO-M1 cells. Activation of NF-κB by stimulators including LPS, poly I:C, hrTNFα, and zymosan was significantly reduced in MIO-M1 cells expressing vMIA. The transduction efficiency of a lentiviral gene delivery vector was not reduced in the presence of vMIA. These results represent the first demonstration of the anti-apoptotic and anti-innate immune signaling capabilities of vMIA in a human retinal cell line. The dual functions of vMIA could provide an effective strategy to treat multiple neurodegenerative diseases and also reduce gene therapy induced ocular inflammation.