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

The properties of the BAF compound were reported in a 1988 landmark paper (31) . BAF is a macrolide antibiotic that inhibits the acid-pumping functions of the vacuolar H Ï© ATPase with high specificity in nanomolar concentrations. Therefore, BAF treatment disrupts the functions of multiple acidic organelles within the central vacuolar system of the cell. Within a decade of the 1988 article, there was a second pivotal paper that reported major impairment of autophagic flux by BAF, namely, BAF treatment prevented fusion between autophagosomes and lysosomes (16) (Fig. 8, pathway I) . This effect was presumed to be caused by the inability of the lysosome to maintain an acidic pH in the presence of BAF. The site of attachment of BAF to the ATPase has been determined (31) . Subsequently, others have found that this BAF effect involves separate inhibitory events on autophagosome-lysosome fusion and autolysosome acidification (32) . Although the autophagic flux studies have received more attention, related BAF studies demonstrated that BAF treatment disrupted the function of the Golgi appara- tus, especially the more acidic trans-Golgi and TGN (33) (Fig. 8, pathway II) . As further proof of its impairment of Golgi apparatus function, several papers reported that BAF treatment interfered with the processing of complex N-linked glycans on enveloped viruses, for example, final processing of the Semliki Forest virus (SFV) and vesicular stomatitis virus (VSV) glycoproteins (34) . Additional virology studies showed failure of influenza A and B virus replication in the presence of several different BAF concentrations (35, 36) . Likewise, replication of HSV-1 was blocked when it was grown in medium containing 100 nM BAF (37) . Taken together, these virology studies clearly showed that one component of the BAF inhibitory effect was impaired envelopment of both RNA and DNA viruses. Similarly, we speculate that BAF treatment of VZV-infected cells drastically reduced the number of virus assembly compartments because of its effects on the TGN (22) .