Orchestrated efforts on host network hijacking: Processes governing virus replication

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

Arrest at the G2/M, G1/S or G0/G1 checkpoint is due to inhibition or delayed activation of CDK1-cyclin B1, CDK2-cyclin E or CDK4/6-cyclin D kinase. Viruses have evolved various strategies to block the formation of these complexes ( Figure 4) . First, some viruses produce proteins to activate CDK inhibitors such as P21 and P27. For instance, human neurotropic polyomaviruses (JCV) produce agnoprotein to cause G2/M arrest through P21 induction [96] ; HBV induces G1/S arrest by modulating the expression of cell cycle-related genes including P21 [97] ; influenza A virus generates multiple viral proteins to induce G0/G1 arrest by increasing P21 expression or preventing its proteasome-mediated degradation [94] ; the P28 protein from murine coronavirus mouse hepatitis virus (MHV) induces G0/G1 arrest by transcriptionally up-regulating P21 [98] ; high P27 level was maintained in the G0/G1 blocked cells after measles virus infection [99] ; and the 3B protein from severe acute respiratory syndrome coronavirus (SARS-CoV) could lead to G0/G1 arrest by interfering with cell cycle regulatory genes including CDK inhibitors [100] . Second, some viruses inhibit complex formation by interacting with cyclins. For instance, parvovirus B19 NS1 protein prevents cyclin B nuclear export and thus leads to G2/M arrest [101] ; HTLV-I encodes a P30 protein which interacts with cyclin E and leads to cell arrest at G1/S phase [102] ; influenza A virus induces G0/G1 arrest by inhibiting cyclin production and stability [94] . Third, some viruses may attract cells in certain states via blocking nuclear transportation or accumulation of CDK-cyclin complexes. For instance, the E4 protein of HPV16 could set cells to G2/M arrest by sequestering the CDK1-cyclin B complex in cytoplasm and preventing it from nuclear entry [103] ; HSV-1 and HSV-2 arrest cell Modulating the expression of viral/cellular genes critical for their life cycle completion. 4) Pushing cells to the phase that provides optimal conditions for virus replication. Cell cycle arrest can be caused by 1) incapable of passing through the checkpoint and entering the next phase or 2) being attracted in or not capable of exiting the current phase. Viruses have developed three strategies to make cells "incapable of passing through the checkpoint": â‘ Inhibiting CDK. Some viruses produce proteins to activate CDK inhibitors. â‘¡Inhibiting cyclin. Some viral proteins interact with cyclins. â‘¢Inhibiting CDK/cyclin complex. Some viruses block nuclear transportation or accumulation of CDK-cyclin complexes. Cell cycle promotion (green) typically pushes cells toward the S phase that provides optimal conditions for virus replication through inhibiting pRb and TP53 signalings. cycle in the G1 phase by reducing the level of functional CDK2-cyclin E complexes after infection [104] .