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Host factors exploited by retroviruses

Nature Reviews Microbiology volume 5, pages 253–263 (2007)Cite this article

Key Points

  • Retroviruses exploit a vast array of host cellular proteins during their replication. Every step in the viral life cycle requires a distinct set of these host factors.

  • Host factors provide attractive targets for therapeutic intervention. The cellular genes encoding these factors would not rapidly mutate to produce drug-resistant variants. Nonspecific inhibition of host machinery, however, could prove toxic.

  • Retroviruses often use transport systems that are involved in the movement of cellular cargoes using cytoskeletal motors, or in vesicle trafficking.

  • Different retroviruses use different sets of host factors.

  • Viruses often use redundant pathways, or use alternative pathways present in particular cell types.

  • Sometimes the viruses disrupt a host process or molecular machine for the purposes of virus replication. For example, the ESCRT machinery, which is normally involved in protein sorting to the endosome, is relocated to the plasma membrane by enveloped viruses and exploited for their budding and release.

  • Genomic screens indicate that the total number of host factors needed by viruses is enormous and that current information about these factors and their roles in virus replication is still incomplete.

Abstract

Retroviruses make a long and complex journey from outside the cell to the nucleus in the early stages of infection, and then an equally long journey back out again in the late stages of infection. Ongoing efforts are identifying an enormous array of cellular proteins that are used by the viruses in the course of their travels. These host factors are potential new targets for therapeutic intervention.

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Figure 1: The retroviral life cycle.
Figure 2: Alternative routes of retroviral entry.
Figure 3: Alternative routes for nuclear entry of retroviral DNA.
Figure 4: Gag trafficking during virion assembly and release.

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Acknowledgements

The themes of viral trafficking presented in this review arose often at a recent Keystone Symposium held in Santa Fe, New Mexico and at the annual Retrovirus meeting at Cold Spring Harbor, USA.

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  1. Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute HHSC 1310c, College of Physicians and Surgeons, Columbia University,

    Stephen P. Goff

  2. Department of Microbiology, Howard Hughes Medical Institute HHSC 1310c, College of Physicians and Surgeons, Columbia University, 701 West 168th Street, New York, 10032, New York, USA

    Stephen P. Goff

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Glossary

Provirus

Retrovirus particles contain an RNA genome, but after infection the RNA is reverse transcribed into DNA, which is inserted into the host-cell genome to form the integrated viral DNA, or provirus. The proviral DNA is a latent form of the virus genome that can be transcribed to produce infectious virus.

Co-receptor

The retroviral envelope proteins facilitate viral entry by binding to specific proteins on the cell surface and fusing the viral and host membranes. In HIV-1, the envelope protein requires two cell proteins: a primary receptor for the initial binding (CD4), and a secondary co-receptor for membrane fusion. Other retroviruses use a single protein for both steps.

Dominant negative

A mutation that impairs or abolishes gene function, called a loss-of-function mutation, is most often recessive to the wild-type, so that cells that contain one mutant and one wild-type copy of the gene function normally. Some mutations are dominant over the wild-type gene and have been named 'dominant negative' or 'dominant interfering', because the mutant gene product interferes with the normal gene-product's function.

SUMOylation

Many proteins are modified by the covalent attachment of SUMO (small ubiquitin-like modifier) on lysine residues. SUMOylation often directs proteins to specific subcellular locations, such as the nucleus or plasma membrane. The modification is reversible by specific proteases and is highly transient.

Central polypurine tract

A retroviral RNA genome contains short stretches of purines, called polypurine tracts (PPTs), near the 3′-end. These PPTs function as RNA primers for plus-strand DNA synthesis during reverse transcription. Complex retroviruses (including HIV-1) contain a second, more centrally located PPT that provides a second site for initiation of DNA synthesis. Reverse transcription forms an overhanging DNA flap in this region, which might form a triple-stranded helix, and which has been proposed to function as a nuclear targeting element.

Internal ribosome entry site

(IRES). Some mRNAs, including many viral RNAs, contain a structured RNA element known as an internal ribosome entry site that is found in the 5′-untranslated region downstream of the cap. The IRES is recognized by translation initiation factors, and allows for cap-independent translation.

Cap-dependent translation

The 5′-end of mRNA typically contains a structure called a 5′-cap, including an inverted guanine residue, and is decorated by multiple methyl modifications. Translation of most mRNAs requires the cap and is initiated by factors that recognize the 5′-cap structure.

RNA pseudoknot

Single-stranded RNA can fold into complex structures that are held together by intramolecular contacts. One such structure, called a pseudoknot (because the backbone chain does not form a true topological knot), consists of two base-paired regions of helical duplexes connected by two unpaired loops.

Membrane raft

A highly dynamic domain in the cellular membrane, which has an altered lipid composition, often with an unusually high or low content of cholesterol. Membrane rafts can acquire distinctive membrane proteins.

Exosome

Secreted proteins are often delivered to the cell surface by a membrane vesicle called an exosome. These small vesicles are formed by budding into late endosomes or multivesicular bodies, which then fuse with the plasma membrane and release the exosomes to the extracellular space.

Polarized cell

Many cells that comprise complex organs, especially those forming layers or sheets, acquire distinctive faces or sides with different membrane compositions. Such cells, with a basolateral membrane facing the basement layer and an apical membrane facing the lumen or external medium, are said to be polarized. Viruses often bud directionally in polarized cells.

Ubiquitinylation

Many proteins are post-translationally modified by the covalent addition of ubiquitin (a small protein tag) on specific lysine residues. The addition of multiple ubiquitins in a polyubiquitin chain is often a signal for accelerated degradation. Addition of a single ubiquitin often directs the re-localization of the target protein into specific intracellular vesicles.

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Goff, S. Host factors exploited by retroviruses. Nat Rev Microbiol 5, 253–263 (2007). https://doi.org/10.1038/nrmicro1541

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