Key Points
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Retroviral Gag proteins encode all the activities that are required for virion assembly and release. These activities include Gag multimerization, interaction with the plasma membrane and encapsidation of the genomic viral RNA.
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Most retroviruses bud at the plasma membrane. In macrophages, HIV-1 assembly can be visualized in complex plasma membrane invaginations.
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Retroviruses induce synaptic structures and filopodial processes to promote their cell-to-cell transfer.
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Retroviral egress requires late-budding activity domains (L-domains) that facilitate the resolution of the membrane stalk connecting the nascent virions to the host cell at the end of assembly. L-domains are short amino acid motifs, encoded by Gag, that recruit the ESCRT pathway, a highly conserved cellular machinery that mediates membrane scission events which resemble the topology observed in retroviral budding.
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The ESCRT machinery is modular in nature, and it can be subverted by enveloped viruses to facilitate viral assembly and release. Recent advances in studies of viral assembly and release have increased our understanding of the mechanisms that are employed by the core ESCRT machinery in membrane deformation and scission.
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The mechanism of action of tetherin, an interferon-induced membrane protein that inhibits the release of mammalian enveloped viruses, has also been elucidated, as well as the countermeasures that HIV-1 and related viruses deploy to inhibit its function.
Abstract
The plasma membrane is the final barrier that enveloped viruses must cross during their egress from the infected cell. Here, we review recent insights into the cell biology of retroviral assembly and release; these insights have driven a new understanding of the host proteins, such as the ESCRT machinery, that are used by retroviruses to promote their final separation from the host cell. We also review antiviral host factors such as tetherin, which can directly inhibit the release of retroviral particles. These studies have illuminated the role of the lipid bilayer as the unexpected target for virus restriction by the innate immune response.
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Acknowledgements
We thank N. Sherer, C. Jolly and M. Agromayor for critical reading of this manuscript, and S. Willey for help with some of the figures. We also acknowledge the many important studies from colleagues in the field that we have been unable cite owing to space constraints. J.M.S. is funded by the UK Lister Institute of Preventive Medicine, the European Molecular Biology Organisation (EMBO) Young Investigator Programme, the UK Medical Research Council (grant number G0802777) and the UK Wellcome Trust (grant number WT093056MA). S.J.D.N. is funded by a UK Wellcome Trust Research Career Development Fellowship (grant number WT082274MA) and the UK Medical Research Council (grant number G0801937).
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Glossary
- Virological synapse
-
An organized structure that forms at the junction between the infected cell and the uninfected target cell. This structure facilitates retroviral transfer in the absence of cell-to-cell fusion.
- Cytonemes
-
Thin membranous bridges that connect two cells in the absence of a cytoplasmic connection.
- ESCRT
-
(Endosomal sorting complex required for transport). A conserved cellular machinery for the sorting of ubiquitylated cargo proteins into vesicles that bud away from the cytoplasm, and the subsequent scission of the membrane neck. This machinery is also required for abscission, the last step in cell division. The recruitment of ESCRT proteins through retroviral late-budding domains (L-domains) is essential for viral assembly.
- Vpu
-
A small integral membrane protein that is encoded by HIV-1. Vpu binds to human tetherin and counteracts its antiviral activity.
- Tetherin
-
A mammalian interferon-induced type II membrane protein that inhibits the release of enveloped viral particles from infected cells.
- Gag
-
A polyprotein encoded by all retroviruses that is processed to form the structural components of the mature viral particle.
- Photoactivatable
-
Pertaining to a fluorescent protein: able to increase in fluorescence when excited by 488 nm light.
- Photoconvertible
-
Pertaining to a fluorescent protein: able to change the emission spectrum on exposure to ultraviolet light.
- Total internal reflection fluorescence microscopy
-
A microscopy technique that is based on the selective illumination of the molecules in a thin section near the coverslip. This technique is particularly suitable to the study of events that occur near or at the plasma membrane.
- Fluorescence resonance energy transfer
-
A phenomenon of quantum mechanics that occurs when a pair of donor and acceptor fluorophores are less than 10 nm from each other, allowing excitation of the acceptor by emission from the donor.
- Fluorescence recovery after photobleaching
-
A technique that consists of photobleaching fluorescent molecules in a defined region of the cell, followed by assessing the recovery of fluorescence in this region. The results provide diffusion coefficients of the fluorescent protein as an indication of its mobility.
- Virus-like particles
-
Non-infectious viral particles that lack viral genetic material.
- Electron tomography
-
An experimental strategy that is based on electron microscopy and allows three-dimensional reconstruction of biological samples.
- Tetraspanins
-
A large group of structurally related, small membrane proteins that share the capacity to associate with themselves and with transmembrane receptors. They control viral infections and several cellular processes, including migration, cell-to-cell fusion and signalling.
- Uropods
-
Cytoplasmic protrusions at the rear of a polarized cell. In activated T cells, uropods are enriched for cell adhesion molecules.
- NEDD4-like HECT ubiquitin ligases
-
A family of E3 ubiquitin ligases that contain WW domains which bind to PPXY-dependent late-budding domains (L-domains) and are required for recruitment of the ESCRT machinery.
- siRNA
-
(Small interfering RNA). A double-stranded, short RNA molecule that induces RNA interference and silencing of a target mRNA.
- HIV-1 group M
-
The major phylogenetic group of HIV-1 that resulted in the HIV/AIDS pandemic. This group was originally derived from a zoonotic transfer of simian immunodeficiency virus from chimpanzees (SIVcpz) to a human. HIV-1 groups N, O and P represent separate zoonotic events, and the spread of these viruses is geographically limited.
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Martin-Serrano, J., Neil, S. Host factors involved in retroviral budding and release. Nat Rev Microbiol 9, 519–531 (2011). https://doi.org/10.1038/nrmicro2596
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DOI: https://doi.org/10.1038/nrmicro2596
