Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr 23;13(5):735.
doi: 10.3390/v13050735.

HIV-1 Entry and Membrane Fusion Inhibitors

Tianshu Xiao  1   2 , Yongfei Cai  1   2 , Bing Chen  1   2
Affiliations
Review

HIV-1 Entry and Membrane Fusion Inhibitors

Tianshu Xiao et al. Viruses. .

Abstract

HIV-1 (human immunodeficiency virus type 1) infection begins with the attachment of the virion to a host cell by its envelope glycoprotein (Env), which subsequently induces fusion of viral and cell membranes to allow viral entry. Upon binding to primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4), Env undergoes large conformational changes and unleashes its fusogenic potential to drive the membrane fusion. The structural biology of HIV-1 Env and its complexes with the cellular receptors not only has advanced our knowledge of the molecular mechanism of how HIV-1 enters the host cells but also provided a structural basis for the rational design of fusion inhibitors as potential antiviral therapeutics. In this review, we summarize our latest understanding of the HIV-1 membrane fusion process and discuss related therapeutic strategies to block viral entry.

Keywords: HIV; envelope glycoprotein; fusion inhibitor; membrane fusion; viral entry.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
HIV-1 (human immunodeficiency virus type 1) envelope glycoprotein and its receptors. (A) The full-length HIV-1 Env, gp160. Segments of gp120 and gp41 include: C1–C5, conserved regions 1–5; V1–V5, variable regions 1–5; F, fusion peptide; HR1, heptad repeat 1; C-C loop, the immunodominant loop with a conserved disulfide; HR2, heptad repeat 2; MPER, membrane proximal external region; TM, transmembrane anchor; CT, cytoplasmic tail; tree-like symbols, glycans. Those for CCR5 include: N, N-terminus; TM1-7, transmembrane helices 1–7; ECL1-3, extracellular loop 1–3; ICL3, intracellular loop 1–3; and CT, cytoplasmic tail. For CD4, they are: D1–4, immunoglobulin (Ig) domain 1–4; TM and CT. (B) Structures of HIV-1 Env. The crystal structure of the unliganded HIV-1 BG505 SOSIP.664 Env trimer (pdb ID: 4ZMJ; [11]) that lacks the MPER, TMD, and CT is shown in the ribbon diagram with gp120 in cyan and gp41 in yellow. Structures of the MPER-TMD and TMD-CT reconstituted in bicelles that mimic lipid bilayer determined by NMR (pdb ID: 6E8W; [12]; pdb ID: 6UJU; [13]). The MPER is in magenta, the TMD in dark red, and the CT in gold. The EM density in gray is 3D reconstruction of the unliganded HIV-1 BaL Env spike on the surface of virion by cryo-electron tomography (EMDB ID: EMD-21412). (C) Crystal structure of soluble four domain CD4 (pdb ID: 1WIO; [14]). D1-D4 and the location of the transmembrane segment (TM) are indicated. (D) Crystal structure of a modified CCR5 in complex with Maraviroc (pdb ID: 4MBS; [15]). CCR5 is shown in the ribbon diagram in brown, the internally fused rubredoxin and the ligand in gray. N-terminus (N), C-terminus (C), and the second extracellular loop (ECL2) are indicated. Crystal structure of an engineered CXCR4 in complex with a viral chemokine antagonist IT1t (pdb ID: 3ODU; [16]). CXCR4 is shown in brown, the fused T4 lysozyme and the ligand in gray.
Figure 2
Figure 2
Env-CD4 interaction. (A) Left, the cryo-EM (cryogenic electron microscopy) structure BG505 DS-SOSIP.664 Env trimer in complex with 4D CD4 and PGT145 Fab (pdb ID: 5U1F; [82]) is shown with gp120 in cyan, gp41 in brown, CD4 in blue and PGT145 Fab in gray. Right, the cryo-EM structure of B41 SOSIP.664 Env trimer in complex with 2D CD4 and 17b (pdb ID: 5VN3; [80]) is shown with gp120 in cyan, gp41 in brown, CD4 in blue, and 17b Fab in gray. (B) Env-CCR5 interaction. Left, overall structure of the 4D CD4-gp120-CCR5 complex (pdb ID: 6MET; [83]) shown in ribbon diagram. N, N-terminus; C, C-terminus; ECL2, extracellular loop 2. V3 loop and the bridging sheet of gp120 are also indicated. Right, close-up views of the interfaces between gp120 and CCR5. The N-terminus of CCR5 is attaching to the surface of the four-stranded bridging β sheet formed by the V1V2 stem and β21–β22 of gp120. Residues Ser7, Pro 8, sulfated Tyr 10, sulfated Tyr14, Tyr15, and Pro19, as well as the disulfide between Cys20 and Cys269 of CCR5 are highlighted in the stick model. The O-linked glycan at Ser7 is also shown. V3 is inserting into the CRS2 of CCR5. The conserved GPGR motif of V3 is highlighted in the stick model, and ECL2 of CCR5 is indicated.
Figure 3
Figure 3
HIV-1 membrane fusion and its inhibition. Top, membrane fusion likely proceeds stepwise as follows. (1) Binding of gp120 to CD4 and a coreceptor allows viral attachment and triggers structural changes in Env. (2) Dissociation of gp120 and insertion of the fusion peptide of gp41 into the target cell membrane leads to the prehairpin intermediate [95]. (3) HR2 folds back onto the inner core of HR1 and brings the two membranes together. (4) A hemifusion stalk forms and resolves into a fusion pore [96]. Bottom, opportunities for fusion inhibitors, including attachment inhibitors targeting the CD4 binding site and the MPER; coreceptor inhibitors; and fusion-intermediate inhibitors.
Figure 4
Figure 4
Fusion inhibitors. Various vulnerable sites of HIV-1 entry, including the BMS compound binding site in gp120 (pdb ID: 5U7M; [142]), the MPER (pdb ID: 6V4T; [147]), the CCR5 TM pocket (pdb ID: 4MBS; [15]), and the T20 binding groove on the HR-1 trimer (pdb ID: 5ZCX; [148]), are targeted by different entry/fusion inhibitors, including BMS-378806, S2C3, Maraviroc, and T20/Enfuvirtide.
Figure 5
Figure 5
Structure of S2C3 in complex with the MPER-TMD. (A) A fluorescence polarization assay for antibody binding to gp41-inter used for the high throughput screen. The binding of a fluoresceinated 2F5 Fab fragment to gp41 can be blocked by hit compounds targeting the MPER by direct competition. F, FITC. (B) Close-up views of the hydrophobic binding pocket of S2C3 formed by residues in the MPER in ribbon diagram (pdb ID: 6V4T; [147]). The MPER is in magenta and S2C3 in green. Residues forming the S2C3 binding pocket are indicated.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Rand R.P., Parsegian V.A. Physical force considerations in model and biological membranes. Can. J. Biochem. Cell Biol. 1984;62:752–759. doi: 10.1139/o84-097. - DOI - PubMed
    1. Parsegian V.A., Fuller N., Rand R.P. Measured work of deformation and repulsion of lecithin bilayers. Proc. Natl. Acad. Sci. USA. 1979;76:2750–2754. doi: 10.1073/pnas.76.6.2750. - DOI - PMC - PubMed
    1. Harrison S.C. Viral membrane fusion. Virology. 2015;479–480:498–507. doi: 10.1016/j.virol.2015.03.043. - DOI - PMC - PubMed
    1. Kielian M. Mechanisms of Virus Membrane Fusion Proteins. Annu. Rev. Virol. 2014;1:171–189. doi: 10.1146/annurev-virology-031413-085521. - DOI - PubMed
    1. Weissenhorn W., Dessen A., Calder L.J., Harrison S.C., Skehel J.J., Wiley D.C. Structural basis for membrane fusion by enveloped viruses. Mol. Membr. Biol. 1999;16:3–9. doi: 10.1080/096876899294706. - DOI - PubMed

Publication types

MeSH terms

Substances