Herpesviruses hijack host exosomes for viral pathogenesis

https://doi.org/10.1016/j.semcdb.2017.03.005Get rights and content

Abstract

Herpesviruses are remarkable pathogens possessing elaborate mechanisms to seize various host cellular components for immune evasion, replication, and virion egress. As viruses are dependent upon their hosts, investigating this intricate interplay has revealed that the exosome pathway is utilised by alpha (Herpes Simplex Virus 1), beta (Human Cytomegalovirus, and Human Herpesvirus 6) and gamma (Epstein-Barr Virus, and Kaposi Sarcoma-associated Herpesvirus) herpesviruses. Virions and exosomes share similar properties and functions. For example, exosomes are small membranous nanovesicles (30–150 nm) released from cells that contain proteins, DNA, and various coding and non-coding RNA species. Given exosomes can shuttle various molecular cargo from a donor to recipient cell, they serve as important vehicles facilitating cell-cell communication. Therefore, exploitation by herpesviruses impacts several aspects of infection including: i) acquisition of molecular machinery for secondary envelopment and viral assembly, ii) export of immune-related host proteins from infected cells, iii) enhancing infection in surrounding cells via transfer of viral proteins, mRNA and miRNA, and iv) regulation of viral protein expression to promote persistence. Studying the dichotomy that exists between host exosomes and herpesviruses has two benefits. Firstly, it will reveal the precise pathogenic mechanisms viruses have evolved, generating knowledge for antiviral development. Secondly, it will shed light upon fundamental exosome characteristics that remain unknown, including cargo selection, protein trafficking, and non-canonical biogenesis.

Section snippets

Extracellular vesicles

Extracellular vesicle (EV) is a broad term encompassing several vesicle types released from cells, that can be further categorised based on size [1], [2]. Apoptotic bodies (1000–5000 nm) are released from cells undergoing apoptosis [3], heterogeneous microvesicles and microparticles (100–1500 nm) can be shed from the plasma membrane [3], [4], [5], and homogenous exosomes (30–150 nm) can also be released from cells by mechanisms described below in Section 1.3 [6], [7]. EVs are secreted by most

Classification

HHVs of the Herpesviridae family emerged 180–220 million years ago [92]. At least eight species of herpesviruses have been found to infect humans, and can be classified into three subfamilies (Table 1). The α-herpesvirinae subfamily (HHV-1, HHV-2, HHV-3) includes HSV-1, HSV-2 and Varicella Zoster Virus (VZV). Herpesviruses are incurable, and only VZV is preventable with a vaccine. Approximately 90% of the world’s population is infected with one or both HSV [93], and can suffer from genital

HHV-1: herpes simplex virus 1

Assembly of herpesviruses has remained a hot topic in viral pathogenic research given the mechanisms are thought to have been conserved for at least 400 million years as the virus and host co-evolved [126]. HSV-1 virion maturation was reported to occur in the cytoplasm where secondary envelopment occurred within Golgi-derived vesicles [127], however the precise molecular mechanism were not characterised until 2007. A study by Crump, Yates, and Minson investigated host proteins involved in

Bridging gaps to understand the roles of exosomes in herpesvirus infection

The complexity of the extracellular microenvironment is supported by the diverse population of membranous vesicles that are continuously released by cells. This variation has confounded the EV field by causing the misinterpretation of data due to co-isolation of contaminating species (e.g. exosomes with shed microvesicles). To safeguard against this, the field has initiated establishing standardized protocols for EV isolation [20], as well as minimum data reporting [19]. These measures will

Concluding remarks

Herpesviruses have evolved elaborate mechanisms to acquire host cell exosomes for several aspects of viral infection. Despite ESCRT components TSG101 and ALIX being among the most studied for exosome biogenesis, herpesviruses do not always engage these for assembly. Rather, HSV-1, HCMV, and HHV-6 utilize other cellular machinery including VPS4, CD63, and CHMPs to promote secondary envelopment. As our knowledge broadens of ESCRT-independent pathways that can be used to generate exosomes, it is

Acknowledgements

Authors are supported, in part, by the National Health and Medical Research Council of Australia Project Grant APP1100737 (RAM), and Early Career CJ Martin FellowshipAPP1037043 (RAM).

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