Orchestrated efforts on host network hijacking: Processes governing virus replication

Dai, Xiaofeng; Hakizimana, Olivier; Zhang, Xuanhao; Kaushik, Aman Chandra; Zhang, Jianying

The cell defense program, i.e. immune response, is primarily suppressed during virus infection. It is well known that certified cells for vaccine or gene therapeutic production such as certified Vero and MDCK cells have defects in their immune defense, e.g. low type I IFN secretion. Immunity can be subverted by autophagy primarily through three mechanisms, i.e. removing endogenous inflammasome agonists [139] , degrading immune mediators such as IRF3 [140] , and inhibiting type I IFN response via inducing mitophagy [141] . Immunity can be prohibited by apoptosis as apoptotic cells induce immunological tolerance [142] . Immunity can be initiated and modulated by lipids given the unique roles of lipid droplets in maintaining cellular mass homeostasis [143] . The two adaptations on cell housekeeping physiology programs, cell cycle alteration and lipid metabolic reprogramming, can be modulated in either way by viruses to create a favorable environment for their replication. Cell cycle arrest at G2/M, G1/S, or G0/G1, or promotion to the S phase is a common feature during the infection of many viruses. The consequences of cell cycle alteration can be very diverse including, e.g. maintaining a replicative state, preventing the passage of damaged DNA to daughter cells, initiating DNA damage repair and/or suppressing immune response. Such a process is typically associated with cell survival programs and regulated by pRB and TP53-mediated signalings [144] ; Cell cycle arrest may lead to less immune response due to reduced cell production [145] . Lipid metabolic reprogramming avails in almost all stages of virus infection, i.e. from initial entry, till replication and assembly, to progeny egress. Lipid droplet, as an energy source, could be produced via cell survival programs to fuel viral production. Autophagy can regulate lipogenesis through modulating the degradation of triglycerides accumulated in cytosolic lipid droplets. Released fatty acids are imported to mitochondria where they undergo β-oxidation to produce ATP for viral replication [146] . Apoptosis is typically accompanied with rapid accumulation of cytoplasmic lipid droplets, by diverting fatty acids away from oxidation to de novo lipogenesis [147] .