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Review
. 2011 Jul 22;410(4):582-608.
doi: 10.1016/j.jmb.2011.04.042.

HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation

Mary Ann Checkley  1 , Benjamin G Luttge, Eric O Freed
Affiliations
Review

HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation

Mary Ann Checkley et al. J Mol Biol. .

Abstract

The HIV-1 envelope (Env) glycoproteins play an essential role in the virus replication cycle by mediating the fusion between viral and cellular membranes during the entry process. The Env glycoproteins are synthesized as a polyprotein precursor (gp160) that is cleaved by cellular proteases to the mature surface glycoprotein gp120 and the transmembrane glycoprotein gp41. During virus assembly, the gp120/gp41 complex is incorporated as heterotrimeric spikes into the lipid bilayer of nascent virions. These gp120/gp41 complexes then initiate the infection process by binding receptor and coreceptor on the surface of target cells. Much is currently known about the HIV-1 Env glycoprotein trafficking pathway and the structure of gp120 and the extracellular domain of gp41. However, the mechanism by which the Env glycoprotein complex is incorporated into virus particles remains incompletely understood. Genetic data support a major role for the cytoplasmic tail of gp41 and the matrix domain of Gag in Env glycoprotein incorporation. Still to be defined are the identities of host cell factors that may promote Env incorporation and the role of specific membrane microdomains in this process. Here, we review our current understanding of HIV-1 Env glycoprotein trafficking and incorporation into virions.

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Figures

Fig. 1
Fig. 1
HIV-1 Env trafficking. Env is synthesized and glycosylated in the rough endoplasmic reticulum (RER) as a 160 kDa precursor protein (gp160), which oligomerizes predominantly into trimers. Precursor Gag (Pr55Gag) is synthesized on cytosolic ribosomes and is directed to the plasma membrane (PM) where it multimerizes in lipid rafts (not shown) to form virus particles. Oligomerized gp160 is transported to the Golgi and trans-Golgi network where it is processed to yield mature SU gp120 and TM gp41. Complexes of gp120-gp41 traffic through the secretory pathway to the PM and are incorporated as trimeric spikes into virus particles. At the PM, endocytosis of Env into early endosomes (EE) occurs via interaction with clathrin adaptor complexes. The internalized Env can either traffic through the late endosomes/multivesicular bodies (LE/MVBs) for degradation in the lysosome, or be returned to the PM through recycling endosomes (not shown). Gag and Env domains are defined in the inset at the top left. Illustration adapted from Ono and Freed with permission from Elsevier.
Fig. 2
Fig. 2
Domains of HIV-1 Env. Precursor gp160 contains the signal peptide (SP), which is cleaved during translation. The remaining precursor is cleaved into the surface subunit (gp120) and transmembrane subunit (gp41) in the Golgi complex at the furin site indicated. gp120 contains five variable domains (V1-V5) and five constant domains (C1-C5). gp41 consists of an extracellular domain, containing the fusion peptide (FP), heptad-repeats (HR1 and HR2), and the membrane-proximal external region (MPER), a transmembrane domain (TMD), and a cytoplasmic tail (CT). An enlarged representation of the gp41 CT is shown to highlight several motifs: the internalization signal YSPL, the Kennedy sequence (ks), the amphipathic α-helices LLP-1, -2, -3, and a C-terminal dileucine motif (LL) involved in endocytosis and intracellular distribution of Env.
Fig. 3
Fig. 3
Schematic representation of gp120 disulfide bonds. Highly conserved cysteine (C) residues in gp120 form disulfide bridges that are important for Env tertiary structure. Variable domains V1-V5 are indicated. Illustration adapted from Leonard et al., originally published in The Journal of Biological Chemistry. © The American Society for Biochemistry and Molecular Biology.
Fig 4
Fig 4
HIV-1 Env gp120 and gp41 structures. (A) Ribbon diagram of gp120 core containing α-helices (α1-5), β-strands (1-25), with relative positions of variable loops (V1-V5) and N and C-termini shown. The orientation of gp120 in this diagram places the viral membrane toward the top and the cell membrane toward the bottom. When gp120 is bound to CD4 it forms a “bridging sheet” consisting of four β-strands, which separates the inner and outer domains of gp120 relative to their orientation in the trimeric complex. Image reprinted by permission from Macmillan Publishers Ltd: Nature, copyright 1998. (B) Ribbon diagram of gp120 core (as in panel A) with N- terminus (red) and gp41 interaction site (blue) shown. The inner domain is shown in red and grey and the outer domain is shown in orange. The bridging sheet, which shares elements from both inner and outer domains, is in grey and orange. (C) Trimeric gp120 (same colors as in panel B) bound to three molecules of CD4 (yellow) and Fab from neutralizing antibody 17b (brown), used to stabilize the gp120 structure, superimposed onto the electron density observed by cryoelectron tomography (light grey). Orientation of this structure rotated 90°, which places the viral membrane in the plane of the page, is also shown on the right. Images (panels B, C) reproduced from Pancera et al. with permission. (D) Three-dimensional representation of HIV-1 Env in its CD4-bound conformation. (Left) A trimeric Env spike (blue) anchored in the lipid bilayer of the viral membrane (grey) is shown. The white arrow indicates the predicted location of gp41. (Right) Ribbon diagram of gp120 core (red) superimposed on the density map (blue) with V1/V2 loop (yellow) and V3 loop (green) shown. Reprinted by permission from Macmillan Publishers Ltd: Nature, copyright 2008.
Fig 5
Fig 5
Models of HIV-1 gp41 CT topology. (Left) Traditional model of the gp41 CT with a single membrane-spanning domain, most likely found in virions. This single-pass model contains the entire CT inside the virion (internal). gp41 domains are the same as indicated in Fig 2. Sites of mutation that confer resistance to AME, which were later shown to become new HIV-1 PR cleavage sites, are indicated (black arrows).,, (Right) Alternative three-membrane-spanning topology of gp41 CT, which exposes portions of the gp41 CT to the extracellular space, may also exist with a detectable frequency in HIV-1 Env-expressing cells in addition to the more traditional model. Illustration adapted from Steckbeck et al.
Fig. 6
Fig. 6
Schematic representation of retroviral TM subunits, indicating the lengths [in amino acids (aa)] of their respective cytoplasmic tails. As illustrated, lentiviral TM CTs tend to be significantly longer than those of other retroviruses, with the exception of feline immunodeficiency virus (FIV). SIVagm, simian immunodeficiency virus from African green monkey; MoMLV, Moloney-MLV; HTLV-1, human T-cell lymphotropic virus type 1. Other viral acronyms are defined in the text.
Fig. 7
Fig. 7
Models for HIV-1 Env incorporation. The passive incorporation model (A) postulates no interaction between Gag and Env. The direct Gag-Env interaction model (B) takes into account evidence that the MA domain of Gag interacts with the CT of gp41. The Gag–Env cotargeting model (C) suggests that Env is enriched in virus assembly domains through lipid raft (brown) association. The indirect Gag–Env interaction model (D) provides an alternative explanation for Env incorporation that involves an adaptor protein that binds both Env and Gag. The association of Gag with lipid rafts in all models is assumed but not shown. The color scheme for Gag and Env is the same as in Fig. 1.
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