Host factors and measles virus replication

doi:10.1016/j.coviro.2012.10.008

Current Opinion in Virology

Volume 2, Issue 6, December 2012, Pages 773-783

https://doi.org/10.1016/j.coviro.2012.10.008 Get rights and content

This review takes a general approach to describing host cell factors that facilitate measles virus (MeV) infection and replication. It relates our current understanding of MeV entry receptors, with emphasis on how these host cell surface proteins contribute to pathogenesis within its host. The roles of SLAM/CD150 lymphocyte receptor and the newly discovered epithelial receptor PVRL4/nectin-4 are highlighted. Host cell factors such as HSP72, Prdx1, tubulin, casein kinase, and actin, which are known to impact viral RNA synthesis and virion assembly, are also discussed. Finally the review describes strategies used by measles virus to circumvent innate immunity and confound the effects of interferon within the host cell. Proteomic studies and genome wide RNAi screens will undoubtedly advance our knowledge in the future.

Highlights

► SLAM/CD150, PVRL4/nectin-4, and CD46/MCP are host cell receptors for MeV. ► HSP72, Prdx1, tubulin, casein kinase, and other cellular kinases are implicated in MeV transcription and replication. ► Glycoprotein sorting signals and actin help mediate virus assembly. ► MeV proteins including P, C, V, and N manipulate components of innate immunity.

Introduction

Measles virus (MeV), a member of the genus Moribillivirus from the Paramyxoviridae family, is a highly pathogenic non-segmented negative-strand RNA virus that causes respiratory distress and immune suppression upon infection of its human host. The disease is characterized by a latent period of 10–14 days followed by early symptoms, which include cough, fever, Koplik's spots, and the appearance of a maculopapular rash, a hallmark of MeV. The onset of rash coincides with the initiation of virus clearance via the immune response in an immunocompetent individual. Complications arise in young children and immunocompromised individuals owing to immune suppression and subsequent susceptibility to secondary infections that could last for weeks to months following resolution of the initial infection.

The MeV genome encodes a membrane-associated matrix (M) protein, the hemagglutinin (H) and fusion (F) envelope glycoproteins, the RNA polymerase-associated phosphoprotein (P) and large polymerase (L) protein, and a nucleocapsid (N) protein that surrounds the viral genome (Figure 1a). The area encoding the P gene includes two overlapping open reading frames that code for the non-structural viral proteins, V and C (Figure 1b). Although these proteins, which are involved in suppression of the host immune response, are dispensable for virus replication in vitro, they are required during natural infections within the host [1]. This review will take a general approach to MeV infection, replication, and interaction of the virus with host cell factors. It will describe our current understanding of MeV attachment factors and entry receptors, with emphasis on how these receptors contribute to virus dissemination and pathogenesis within its host. Host factors involved in RNA synthesis and virus assembly will also be discussed. Finally, the review will highlight virus strategies to circumvent the immune response within the host.

Section snippets

Host receptors involved in measles virus entry

Three known entry receptors have been identified to date for both laboratory-adapted strains and clinical isolates of MeV. CD46 (membrane cofactor protein, MCP) was initially shown to be an entry receptor for vaccine and laboratory-adapted strains of the virus [2•, 3•]. This cell surface marker is expressed on nearly all nucleated human cells and protects the host cell from damage by complement [4]. Clinically relevant isolates of MeV enter the cells via two known receptors, CD150/signaling

Host factors involved in MeV RNA synthesis and assembly

Like other Paramyxoviridae, transcription of the MeV genome starts immediately following entry into the cytoplasm of a cell using the RNA-dependent RNA polymerase (RdRp) associated with the genome (Figure 1b) [34]. The 3′ leader sequence contains recognition sites for the RdRp that sequentially transcribes the viral genes. The RdRp may detach from the ribonucleoprotein (RNP) complex within the intergenic regions that separate viral genes, creating a transcription gradient where genes that are

Measles virus overcomes host factors involved in innate immunity

During infections by MeV, manipulation of the host immune response plays a key role in pathogenesis [61]. The interplay between host innate immunity and counteracting measures by the virus influences the outcome of infection. In turn, virus mediated effects on innate immunity have profound consequences upon the development of adaptive immunity within the host [62, 63, 64]. Immune suppression is a key consequence of MeV owing to the infection of activated B cells, T cells, dendritic cells, and

Conclusions

Host cell factors impact all stages of virus infection, viral nucleic acid synthesis, virion assembly, and evasion of the host innate immune system. Our understanding of MeV tropism and pathogenesis has greatly improved owing to the discovery of the host cellular attachment factors and entry receptors described here. The role of nectin-4/PVRL4, along with other host factors in MeV infection of the CNS, still requires further investigation. A number of host factors have also been implicated in

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

This work was supported by grants from the Canadian Institute for Health Research (CIHR MOP 10638; CIHR MOP 114949) and Nova Scotia Health Research Foundation (Grant #1200). C.D.R. is a Canada Research Chair (Tier I) in Vaccinology and Viral Therapeutics. R.S.N. is supported by a CIHR Banting Postdoctoral Fellowship and held a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by the Canadian Breast Cancer Foundation – Atlantic Region as part of The Terry Fox

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^*: These authors contributed equally to this work.

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