Herpesvirus and Autophagy: “All Right, Everybody Be Cool, This Is a Robbery!”

Abstract

Autophagy is an essential vacuolar process of the cell, leading to lysosomal degradation and recycling of proteins and organelles, which is extremely important in maintaining homeostasis. Multiple roles have been now associated with autophagy, in particular a pro-survival role in nutrient starvation or in stressful environments, a role in life span extension, in development, or in innate and adaptive immunity. This cellular process can also take over microorganisms or viral proteins inside autophagosomes and degrade them directly in autolysosomes and is then called xenophagy and virophagy, respectively. Several Herpesviruses have developed strategies to escape this degradation, by expression of specific anti-autophagic proteins. However, we are increasingly discovering that Herpesviruses hijack autophagy, rather than just fight it. This beneficial effect is obvious since inhibition of autophagy will lead to decreased viral titers for human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) or Varicella-Zoster virus (VZV), for example. Conversely, autophagy stimulation will improve viral multiplication. The autophagic machinery can be used in whole or in part, and can optimize viral propagation or persistence. Some viruses block maturation of autophagosomes to avoid the degradation step, then autophagosomal membranes are used to contribute to the envelopment and/or the egress of viral particles. On the other hand, VZV stimulates the whole process of autophagy to subvert it in order to use vesicles containing ATG (autophagy-related) proteins and resembling amphisomes for their transport in the cytoplasm. During latency, autophagy can also be activated by latent proteins encoded by different oncogenic Herpesviruses to promote cell survival and achieve long term viral persistence in vivo. Finally, reactivation of gammaherpesvirus Murid Herpesvirus 68 (MHV68) in mice appears to be positively modulated by autophagy, in order to control the level of inflammation. Therefore, Herpesviruses appear to behave more like thieves than fugitives.

The ICP0 Protein of Herpes Simplex Virus 1 (HSV-1) Downregulates Major Autophagy Adaptor Proteins Sequestosome 1 and Optineurin during the Early Stages of HSV-1 Infection

“…To successfully colonize a host, HSV-1 must overcome the immune barriers of the human body, and for this, it has evolved multiple strategies, including the ability to block autophagy (2)(3)(4)(5)(6)(7). Autophagy is a process for selective degradation of cellular components that serves as a homeostatic mechanism of the cells (8)(9)(10)(11).…”

“…For example, autophagy removes bacteria that escape the phagosomal compartment upon phagocytosis and damaged bacterium-containing phagosomes (9,10,19,20). Virions in the cytoplasm of cells or viral components are removed via a process called virophagy (4,(21)(22)(23).…”

Autophagy, EVs, and Infections: A Perfect Question for a Perfect Time

“…Early infection by HCMV was also shown to stimulate autophagy while simultaneously blocking autophagosome degradation (McFarlane et al, 2011 ; Chaumorcel et al, 2012 ; Mouna et al, 2016 ). This strategy, similar to some RNA viruses described in the previous section, has been postulated to help the virus utilize autophagic membranes for its replication (Lussignol and Esclatine, 2017 ), although further study will likely be required to dissect out the true role of autophagy in this scenario. Additionally, gammaherpesviruses have been shown to also induce autophagy in a stage-dependent manner.…”

“…However, while prior evidences indicated that herpesviruses in general prefer to inhibit autophagy, more recent data has implicated additional pro-viral roles for autophagic pathways. For example, the production of several herpesviruses including HSV-1, HCMV, and Varicella-Zoster virus (VZV) has been shown to be aided by functioning autophagy (Lussignol and Esclatine, 2017 ). Early activation of autophagy by HSV-1 was proposed to help entry of the virus into host cells, as indicated by decreased viral titers in cells pre-treated with autophagy inhibitors (Siracusano et al, 2016 ).…”

Epstein–Barr Virus BALF0 and BALF1 Modulate Autophagy

“…Autophagy also emerged as an alternative pathway to present microbial antigens to the immune system [2]. Accordingly, some pathogens have evolved successful strategies to escape immune control or promote their replication by manipulating autophagy for their own benefit [3,4].…”