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Review
.2015 Aug;13(8):484-96.
doi: 10.1038/nrmicro3490. Epub 2015 Jun 29.

HIV-1 assembly, release and maturation

Affiliations
Review

HIV-1 assembly, release and maturation

Eric O Freed. Nat Rev Microbiol.2015 Aug.

Abstract

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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Conflict of interest statement

Competing interests statement

The author declares no competing interests.

Figures

Figure 1 |
Figure 1 |. The late stages of the HIV-1 replication cycle.
The viral envelope (Env) glycoproteins traffic via the secretory pathway, from the rough endoplasmic reticulum (RER) to the Golgi and then in vesicles until they arrive at the plasma membrane. The Gag precursor polyprotein — which contains the matrix (MA), capsid (CA), nucleocapsid (NC) and p6 domains — is synthesized in the cytosol from full-length viral RNA. The GagPol precursor polyprotein — which contains MA, CA, NC, protease, reverse transcriptase and integrase domains — is synthesized as the result of a programmed frameshifting event during the translation of Gag-encoding viral RNA. Gag recruits the viral genomic RNA, begins to multimerize and reaches the plasma membrane by a still-undefined pathway. Gag is anchored to the plasma membrane in lipid raft microdomains via insertion of its amino-terminal myristate into the lipid bilayer and by direct interactions with the phospholipid phosphatidylinositol-(4,5)-bisphosphate. The assembling particle incorporates Env and then recruits endosomal sorting complex required for transport I (ESCRT-I)via a direct association between the PTAP motif in p6 and the tumour susceptibility gene 101 (TSG101) subunit of ESCRT-I. Gag also engages in direct binding with the ESCRT-associated factor ALG2-interacting protein X(ALIX), primarily through the YPXL motif in p6. As the budding process proceeds, the ESCRT-III and vacuolar protein sorting 4 (VPS4) complexes are recruited and drive the membrane scission reaction that leads to particle release. Maturation, which leads to the formation of the conical capsid core, is triggered by proteolytic cleavage of the Gag and GagPol polyprotein precursors by the viral protease.
Figure 2 |
Figure 2 |. Gag structure and functions.
High-resolution structures of the major domains of Gag — matrix (MA), capsid (CA), nucleocapsid (NC) and p6 — are presented over a linear depiction of the Gag precursor polyprotein. The major functions of each Gag domain are indicated. MA (Protein Data Bank (PDB) accession1HIW) is involved in Gag targeting and binding to the plasma membrane, and in incorporation of the envelope (Env) glycoprotein. Membrane binding requires amino-terminal myristylation (Myr). CA (PDB accession2M8N) participates in Gag assembly, formation of the conical capsid core and regulation of the nuclear import of viral DNA. The CA N-terminal domain (CANTD) contains an N-terminal β-hairpin and a proline-rich loop that binds the host protein cyclophilin A (CYPA); the CA carboxy-terminal domain (CACTD) contains the major homology region (MHR). CANTD andCActd are connected by a short, flexible interdomain linker. Spacer peptide 1 (SP1) is involved in Gag assembly. NC (PDB accession1BJ6) contains two zinc-finger domains; it participates in Gag assembly and RNA encapsidation, and serves as an RNA chaperone. p6 (PDB accession2C55) is involved in recruitment of the endosomal sorting complex required for transport (ESCRT) components and in Vpr incorporation.
Figure 3 |
Figure 3 |. Models of viral envelope glycoprotein incorporation.
Several non-mutually exclusive mechanisms may participate in the incorporation of the viral envelope (Env) glycoproteins into new virions.a | Env expressed on the cell surface might be incorporated passively into virions as the particles acquire host-derived membrane during assembly and budding.b | In a putative Gag-Env co-targeting mechanism, both Gag and Env are targeted to a specific site on the plasma membrane (for example, a lipid raft microdomain), allowing Env to be concentrated at sites of assembly.c | Evidence suggests that the matrix (MA) domain of Gag and the cytoplasmic tail of the gp41 subunit of Env interact directly, resulting in the retention of Env complexes at sites of budding and their recruitment into virions.d | The MA domain of Gag and the cytoplasmic tail of gp41 could interact indirectly, with a host protein bridging the two viral proteins. CA, capsid; NC, nucleocapsid. Figure adapted from REF , Elsevier.
Figure 4 |
Figure 4 |. HIV-1 budding and release.
Models for membrane scission mediated by endosomal sorting complex required for transport III (ESCRT-III). In both models, the HIV-1 Gag protein interacts with ESCRT-I and ALG2-interacting protein X(ALIX), which recruit ESCRT-III. Membrane scission is driven by ESCRT-III polymerization in concert with the activity of the AAA ATPase vacuolar protein sorting 4 (VPS4).a | In the first model, ESCRT-III is localized within the budding particle.b | In the second model, ESCRT-I and ALIX are located within the budding particle and recruit ESCRT-III and VPS4, which are mostly located outside the budding particle. Env, envelope. Parta adapted from Van Engelenburg, S. B.et al. Distribution of ESCRT machinery at HIV assembly sites reveals virus scaffolding of ESCRT subunits.Science343,653–656 (2014). Reprinted with permission from AAAS. Partb adapted from REF ,© Cashikaret al.
Figure 5 |
Figure 5 |. HIV-1 maturation.
During virus release, the viral protease cleaves a number of sites in both the Gag and GagPol polyproteins to trigger virus maturation, resulting in major changes in virion morphology, includin g the generation of the conical capsid core.a | A cryoelectron tomogram (left panel), an illustration (middle panel) and a cryoelectron tomography (cryo-ET) reconstruction (right panel) of the immature HIV-1 virion, together with a zoomed-in view of the immature Gag lattice (far-right inset). In the far-right panel, the capsid (CA) amino-terminal domain (CANTD) is depicted in blue and the CA carboxy-terminal domain (CActd) is in orange.b | A cryoelectron tomogram (left panel), an illustration (middle panel) and a cryo-ET reconstruction (right panel) of the mature HIV-1 virion, together with a zoomed-in view of the mature CA lattice (far-right inset; the CANTD and CACTD are coloured as in parta).c | The all-atom structure of an HIV-1 capsid core, with CA pentamers (green) in the otherwise hexameric lattice.d | A cryo-ET reconstruction of a virion produced from cells treated with the maturation inhibitor bevirimat, showing disruption of capsid formation. Env, envelope; MA, matrix; NC, nucleocapsid. Cryoelectron tomograms in parta andb reproduced from REF. , Elsevier. Cryo-ET reconstructions in partsa,b andd republished with permission of the American Society for Microbiology, from HIV 1 maturation inhibitor bevirimat stabilizes the immature Gag lattice. Keller, P. W.et al. 85, 4, 2015; permission conveyed through Copyright Clearance Center. Zoomed-in views in parts a and b reproduced from REF , Nature Publishing Group. Partc reproduced from REF , Nature Publishing Group.
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