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Avoiding the void: cell-to-cell spread of human viruses

Key Points

  • The generally accepted form of animal virus dissemination between and within hosts is through the release of viral particles that diffuse from the infected cell and subsequently attach to and enter new, permissive target cells. However, viruses from many families can also spread directly between contacting cells, and these viruses have evolved diverse and ingenious mechanisms for achieving this spread. Cell-to-cell spread can enable viruses to evade the humoral immune response. This Review discusses the following aspects of direct cell-to-cell viral spread.

  • The general principles of how viruses move between target cells and tissues, and why some viruses can achieve direct cell-to-cell spread whereas others cannot, including the advantages and disadvantages to viral pathogens of dissemination through fluid-phase dissemination as opposed to direct cell-to-cell spread are discussed.

  • The cellular receptors used by viruses to enter target cells are discussed. Receptor use can affect the type of tissue infected and the mode of viral spread. The viral envelope glycoproteins involved in receptor binding that determine viral tropism are reviewed, and mechanisms of viral dissemination explained.

  • Cell polarity influences viral exit from cells, and how this impacts the mode of viral spread and pathogenesis is explained. Some retroviruses are able to spread from cell to cell by inducing polarity in immune cells that do not have constitutive polarity.

  • Some viruses fuse contacting cell plasma membranes, which can contribute to viral spread. Other viruses subvert the host cell cytoskeleton to aid in their cell-to-cell spread.

  • Some viruses travel within the nervous system through neural synaptic transmission.

  • Cell-to-cell spread can enable viruses to evade the humoral immune response, and might be important in viral evasion of intrinsic resistance factors, genome-wide analyses of virus and host cell gene function in cell-to-cell spread, as well as the search for novel targets for drug design and intervention.

Abstract

The initial stages of animal virus infection are generally described as the binding of free virions to permissive target cells followed by entry and replication. Although this route of infection is undoubtedly important, many viruses that are pathogenic for humans, including HIV-1, herpes simplex virus and measles, can also move between cells without diffusing through the extracellular environment. Cell-to-cell spread not only facilitates rapid viral dissemination, but may also promote immune evasion and influence disease. This Review discusses the various mechanisms by which viruses move directly between cells and the implications of this for viral dissemination and pathogenesis.

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Figure 1: The generally accepted paradigm of virus infection.
Figure 2: Mechanisms of virus cell-to-cell spread.
Figure 3: Two modes of herpesvirus cell-to-cell spread.
Figure 4: Interaction of viruses with actin-containing structures.
Figure 5: Anatomy of a retroviral virological synapse.

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Acknowledgements

The author thanks D. Davis, M. Way, C. Jolly, P. J. Klasse and D. Johnson for reading the manuscript and for suggesting ideas. The author regrets that much important work could not be reviewed or cited because of space restrictions. The author is a Jenner Institute Fellow and his laboratory is supported by grants from the Medical Research Council (MRC), The Wellcome Trust, The International AIDS Vaccine Initiative, The Bill and Melinda Gates Foundation and the European Union.

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DATABASES

Entrez Genome

ASFV

HCV

HIV-1

HSV-1

MLV

MV

RSV

RV

VV

HCV

Entrez Protein

F11L

ICAM1

RhoA

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Glossary

Desquamated skin scale

A flake of dead skin.

Sialic acid

A terminal monosaccharide group on a cell-surface glycoprotein that imparts a negative charge and acts as a binding site for influenza virus.

Syncytium

A giant, multinucleated cell formed through the fusion of two or more cell plasma membranes.

Actin tail

Actin is a component of the cytoskeleton that acts to give cells shape and to mediate membrane motility. Actin tails are columns of clustered, branched actin fibres that propel poxviruses away from the plasma membrane of an infected cell.

Neuromuscular junction

The junction between a neuron and muscle that transforms nerve signals into motor activity.

Varicosity

An enlarged region of a vessel; in this case, a neural axon.

Secondary lymphoid tissue

Allows lymphocytes to communicate with antigen-presenting cells and divide in response to activation signals. Secondary lymphoid tissue is distinct from primary lymphoid tissue, which is the site of lymphocyte production.

Microtubule organizing centre

Microtubules are part of the cytoskeleton and are involved in giving cells shape, in the transport of cargo (including viruses and viral components) within the cell, and in processes such as cell division. The microtubule organizing centre is the site of microtubule nucleation and is found close to the nucleus.

Dendritic cell

A cell that forms part of the mammalian immune system. Dendritic cells detect pathogens and engulf and digest them, and present the pathogen fragments to cells of the adaptive immune system, such as T lymphocytes.

Cytidine deaminases

A family of enzymes that are involved in modifying nucleic acids to introduce mutations into the genetic code. This function allows the immune system to introduce variety into antibody responses and acts as an intrinsic cellular defence against infection by some viruses.

Trim family

A family of proteins that are involved in various cellular processes and can have anti-retroviral properties.

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Sattentau, Q. Avoiding the void: cell-to-cell spread of human viruses. Nat Rev Microbiol 6, 815–826 (2008). https://doi.org/10.1038/nrmicro1972

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