The HIV-1 Gag polyprotein precursor is necessary and sufficient for the formation of virus-like particles in Gag-expressing cells. Gag contains domains that are required for virus assembly and release: the matrix (MA) domain directs Gag to the plasma membrane and promotes the incorporation of the viral envelope (Env) glycoproteins; the capsid (CA) domain drives Gag–Gag interactions during assembly; the nucleocapsid (NC) domain packages the viral genomic RNA; and the p6 domain is required for efficient particle release.
HIV-1 recruits several host factors to promote virus assembly and release. For example, the endosomal sorting complex required for transport (ESCRT) machinery is recruited by the p6 domain of Gag to mediate the pinching off of virus particles from the cell.
Shortly after virus release from the cell, the viral protease cleaves the Gag precursor into the mature Gag proteins MA, CA, NC and p6. Gag processing is a highly ordered multistep sequential process that triggers the morphological rearrangement of viral protein structure, which is known as maturation.
The Gag protein has been the focus of drug discovery efforts aimed at developing inhibitors that are distinct from those targeting the viral enzymes protease, reverse transcriptase and integrase. Of particular promise are small-molecule inhibitors of capsid function, and maturation inhibitors, which target a late step in Gag processing.
Major advances have occurred in recent years in our understanding of HIV-1 assembly, release and maturation, as work in this field has been propelled forwards by developments in imaging technology, structural biology, and cell and molecular biology. This increase in basic knowledge is being applied to the development of novel inhibitors designed to target various aspects of virus assembly and maturation. This Review highlights recent progress in elucidating the late stages of the HIV-1 replication cycle and the related interplay between virology, cell and molecular biology, and drug discovery.
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The author thanks A. Ono, W.-S. Hu, S. Van Engelenburg and members of the Freed laboratory for critical review of the manuscript and helpful discussions. Work in the Freed laboratory is supported by the Intramural Research Program of the Center for Cancer Research (National Cancer Institute, US National Institutes of Health (NIH)) and by the Intramural AIDS Targeted Antiviral Program of the NIH.
The author declares no competing financial interests.
The electron-dense structure at the centre of the mature virus particle. The capsid is composed of an outer layer of capsid protein surrounding the viral RNA genome and the viral enzymes reverse transcriptase and integrase.
The morphological transition from the immature virus particle, in which uncleaved Gag proteins are aligned in a radial manner inside the viral membrane, to the mature particle, which contains a condensed, conical core.
- Envelope glycoproteins
(Env glycoproteins). The heterotrimeric complexes of surface glycoprotein (gp120) and transmembrane glycoprotein (gp41) that are packaged into the viral membrane and mediate receptor–co-receptor binding and fusion in the next round of infection.
The process by which viral proteins and nucleic acids come together in an infected cell to produce new virus particles.
The viral enzyme that cleaves multiple sites in Gag and GagPol during maturation.
- Reverse transcriptase
The viral enzyme that converts the single-stranded viral RNA genome to double-stranded DNA after virus entry into the cell.
The viral enzyme that is responsible for catalysing the insertion of the newly synthesized viral DNA into the host cell genome.
- Endosomal sorting complex required for transport
(ESCRT). A multi-complex machinery that comprises ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III, and that promotes membrane scission reactions (for example, during vesicle budding, cytokinesis and enveloped-virus budding).
- 310 helix
A structural element within a protein; it is composed of a right-handed helix with three residues per turn, in which the first and third residues hydrogen bond with each other. The 310 helix is more tightly wound than the more common α-helix.
- Cyclophilin A
(CYPA). A member of the family of peptidyl prolyl isomerases that facilitate protein folding.
- Multivesicular body
(MVB). A late endosome containing intraluminal vesicles.
(PtdIns(4,5)P2). A phospholipid that plays an important part in the association of HIV-1 Gag with the inner leaflet of the plasma membrane.
- Virus-like particles
(VLPs). Non-infectious particles formed by the expression of Gag alone, or newly budded particles before maturation.
- Maturation inhibitors
Small molecules that block virus maturation by preventing a specific late step in the Gag processing cascade.
- Late domains
Small peptide motifs in retroviral Gag proteins that recruit cellular machinery (that is, endosomal sorting complexes required for transport) to the site of budding to promote virus release.
A cellular protein that is implicated in endothelial cell migration and in the formation of tight junctions.
- Fullerene-like geometry
The structural arrangement of atoms as observed in certain elemental forms of carbon; in their spherical arrangement, fullerenes (such as buckminsterfullerene) are composed of hexagonal rings of carbon with 12 pentameric rings, allowing the structure to adopt a closed conformation. An analogous arrangement of hexameric and pentameric rings is observed in the soccer ball (football, for the non-American reader) and in the retroviral core.
- Hydrocarbon stapling
A chemical method of circularizing peptides, thereby stabilizing their conformation and enhancing their cellular penetration.
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Freed, E. HIV-1 assembly, release and maturation. Nat Rev Microbiol 13, 484–496 (2015). https://doi.org/10.1038/nrmicro3490
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