Elsevier

Current Opinion in Virology

Volume 15, December 2015, Pages 34-40
Current Opinion in Virology

Host entry by gamma-herpesviruses  lessons from animal viruses?

https://doi.org/10.1016/j.coviro.2015.07.007Get rights and content

Highlights

  • There is no good evidence for oral gammaherpesvirus entry.

  • Animal viruses can help us to decipher their human counterparts.

  • MuHV-4 enters new hosts via the olfactory neuroepithelium.

  • It exploits immune communication routes to access B cells and spread.

  • It enters and exits at distinct sites.

The oncogenicity of gamma-herpesviruses (γHVs) motivates efforts to control them and their persistence makes early events key targets for intervention. Human γHVs are often assumed to enter naive hosts orally and infect B cells directly. However, neither assumption is supported by direct evidence, and vaccination with the Epstein-Barr virus (EBV) gp350, to block virion binding to B cells, failed to reduce infection rates. Thus, there is a need to re-evaluate assumptions about γHV host entry. Given the difficulty of analysing early human infections, potentially much can be learned from animal models. Genomic comparisons argue that γHVs colonized mammals long before humans speciation, and so that human γHVs are unlikely to differ dramatically in behaviour from those of other mammals. Murid Herpesvirus-4 (MuHV-4), which like EBV and the Kaposi's Sarcoma-associated Herpesvirus (KSHV) persists in memory B cells, enters new hosts via olfactory neurons and exploits myeloid cells to spread. Integrating these data with existing knowledge of human and veterinary γHVs suggests a new model of host entry, with potentially important implications for infection control.

Section snippets

The problems of γHV infection

All human populations carry γHVs. EBV causes inter alia the commonest childhood cancer of sub-Saharan Africa (Burkitt's lymphoma), nasopharyngeal carcinoma (which accounts for 18% of cancers in China), Hodgkin's disease, post-transplant lymphoproliferative disorder and infectious mononucleosis (IM) [1]. KSHV causes Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Therefore preventing γHV infections would benefit human health. Empirical vaccines have not done

EBV and KSHV host entry

EBV and KSHV are shed in saliva [3, 4]. The key unknown is how salivary virions then enter new hosts. The textbook description ‘EBV infection begins in the oral cavity’ may not be correct. First, there are fundamental questions about how oral entry would work. Mammals, armoured in dead cells, offer few entry routes, so those available tend to be multiply exploited. Oropharyngeal infection lacks an obvious precedent. Viruses known to enter orally  for example, rotaviruses  resist destruction by

Veterinary γHV host entry

Salivary and nasal shedding are well established for Ovine herpesvirus-2 and Alcelaphine herpesvirus-1, which cause malignant catarrhal fever in domesticated ungulates [19]. Transmission occurs orally or nasally via contaminated grazing sites, and nebulized virus infects [20]. Equid herpesvirus 5 causes respiratory disease [21], can be recovered from the respiratory tract [22], and experimentally infects the lungs [23]. Bovine herpesvirus 4 (BoHV-4) infects the respiratory tract [24], and

The MuHV-4 infection model

Mice provide genetically more distant but more tractable hosts, with better genetic and microbiological definition. EBV and KSHV do not realistically infect even mice ‘humanized’ by haematopoietic transplant, so analysis has focussed on MuHV-4 (strain MHV-68) [29, 30, 31•], a γHV first described as infecting bank voles (Myodes glareolus) and yellow-necked mice (Apodemus flavicollis) [32]. Subsequent isolates have all come from yellow-necked mice [33] and a closely related virus was isolated

MuHV-4 olfactory host entry

MuHV-4 given nasally under anaesthesia infects lung epithelial cells via macrophages [39]; when inhaled without anaesthesia, it infects only the nose before spreading to lymphoid tissue [40]; and oral virus is non-infectious unless it spills into the respiratory tract. Therefore host entry is respiratory rather than oral, and probably nasal. Here, MuHV-4 targets olfactory neurons and sustentacular cells [41••], suggesting that it exploits olfactory sampling, a behaviour that has evolved to

Receptor binding and γHV host entry

MuHV-4 binds to heparan via its gp70 [47] and gH/gL [48], and this binding is important for host entry [49]. The MuHV-4 gp150 binds heparan weakly [47] but inhibits heparan-independent binding and so increases virion heparan-dependence [50]. Its homolog in BoHV-4, gp180, also binds to heparan and inhibits heparan-independent binding [51]. Epithelial cells produce full-length gp180, while myeloid cells produce a truncated form [52], so epithelial-derived BoHV-4 is heparan-dependent. As

Viral spread from the olfactory epithelium

HSV-1 penetrates the olfactory epithelium to reach trigeminal neurons [60]. MuHV-4 can follow the same route, and was first isolated from trigeminal ganglia [32], but spreads mainly to B cells in draining lymph nodes (Figure 1). Direct B cell infection is hypothesized for EBV because IM features B cell infection and virions from tumour cells are mainly B cell-tropic. However IM occurs well after host entry; some EBV strains are more epithelial-tropic [77]; and some nasal sinus epithelial cells

Summary

γHV host entry has long been mysterious because it precedes clinical presentation. MuHV-4 has provided new insights: respiratory rather than oral infection; olfactory targeting; B cell access via myeloid cells; and distinct host entry and exit sites. Murine data can only suggest conclusions for human γHVs, but HSV-1 also targets the murine olfactory epithelium, and ungulate γHVs show that respiratory infection is not confined to mice. EBV does not bind to heparan, but there remain reasons to

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Thanks are due to many people who have contributed to studies of γHV host colonization, particularly Ricardo Milho and Janet May (University of Cambridge) and Bénédicte Machiels, Céline Lété and Sylvie François (University of Liège). LG is supported by VIR-IMPRINT ARC of the University of Liège and grants of the FRS-FNRS. PGS is an ARC Future Fellow and is supported also by NHMRC grants 1060138, 1064015 and 1079180. Collaboration between the authors is supported by the BELVIR IAP programme of

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