Divergent Roles of Autophagy in Virus Infection

Chiramel, Abhilash I.; Brady, Nathan R.; Bartenschlager, Ralf

As opposed to Sindbis virus and HCV, a number of viruses have evolved strategies to interfere with -herpesvirus 68 (MHV68) and Herpes Simplex virus 1 (HSV-1) target Beclin-1, thereby inhibiting autophagosome formation. These viruses encode proteins that competitively bind to Beclin-1 and thus inhibit its interaction with Vps34. KSHV encodes a viral Bcl-2 homologue, which binds Beclin-1 with much higher affinity than cellular Bcl-2, thereby preventing incorporation of Beclin-1 into Vsp34 complexes [38] . M11, the viral Bcl-2 homologue encoded by MHV68, also interacts with Beclin-1 and inhibits autophagosome formation [39] . In the case of HSV-1, the virally encoded protein ICP34.5 interacts with Beclin-1 via a 20 amino acid residues-long region (aa 68-87) to inhibit autophagosome biogenesis [40] . Interestingly, deletion of ICP34.5 leads to accumulation of HSV-1 particles in autophagosome-like structures, which can be visualized by electron microscopy [41] . Other viruse,s such as human immunodeficiency virus-1 (HIV-1), influenza A virus (FluAv), coxsackievirus B3 (CVB3) and poliovirus inhibit autophagy by blocking autophagosome maturation or degradation. In the case of HIV-1 and FluAv, the viral proteins Nef and M2, respectively, block autophagosome maturation by a still poorly defined mechanism that depends on their interaction with Beclin-1 [27, 28] . Studies with CVB3 and poliovirus show that autophagy is inhibited at the stage of autolysosomal degradation [18] . Moreover, in the case of coxsackievirus B3 (CVB3) [25, 42] , it was demonstrated that protein levels of LC3-II and p62 increase over time, suggesting that viral infection leads to an accumulation of autophagosomes due to a block in autolysosomal degradation [25, 42] . However, it remains to be determined how these viruses specifically target autolysosomal degradation.