Progeny Varicella-Zoster Virus Capsids Exit the Nucleus but Never Undergo Secondary Envelopment during Autophagic Flux Inhibition by Bafilomycin A1

Girsch, James H.; Walters, Katherine; Jackson, Wallen; Grose, Charles

Cells exhibit basal levels of autophagy even during herpesvirus infection (13) . However, the levels of autophagy induced by VZV infection in both (i) human skin during the VZV disease called herpes zoster (shingles) and (ii) human skin explants in either the skin organ culture model or the severe combined immunodeficient mouse model of VZV infection are far above basal levels (10) . Further, we found that inhibition of autophagy diminishes VZV cell-to-cell spread and infectivity (8) . We also found evidence that an intact autophagy pathway is required for VZV exocytosis after secondary envelopment (14) . Because of these findings, we postulated that treatment of VZV-infected cultures with the antiautophagic flux drug bafilomycin A1 (BAF) would decrease viral titers. BAF is known to interrupt late stages of flux, which include fusion of the autophagosome with both lysosomes and endosomes (15, 16) , as well as fusion of an early endosome with a late endosome (17) . Although we did find that treatment with BAF diminished VZV titers, the findings by electron microscopy were both unexpected and insightful. We also correlate the inhibitory BAF-related effects during the VZV infectious cycle with published data about the inhibitory effects of brefeldin A and monensin at two other Golgi apparatus locations during PRV and HSV-1 infectious cycles. Thus, this report not only reaffirms the centrality of the Golgi apparatus/trans-Golgi network (TGN) as a platform in the alphaherpesvirus infectious cycle, but also expands the antiherpesviral properties of BAF.