Table 1.
Viral entry glycoprotein-mediated immune evasion strategies in other viral families.
Figure 1.
(A) Processing of EBOV glycoproteins. The EBOV genome contains seven genes (3′-NP-VP35-VP40-GP-VP30-VP24-L-5′), but nine proteins are produced due to editing events in the GP gene. The GP gene primary transcript encodes for a ∼110 kDa, dimeric secreted GP (pre-sGP). Furin cleavage of pre-sGP produces mature sGP and a secreted Δ-peptide. Transcriptional stuttering results in the production of the envelope-attached GP and a small, secreted GP (ssGP). The GP is the only virally encoded protein on the EBOV surface and is cleaved by furin to form a disulfide-linked GP1-GP2 heterodimer, which then assembles as trimers on the virus surface. GP1 contains the receptor-binding site for host cell attachment, while GP2 contains a helical heptad-repeat (HR) region, transmembrane anchor (TM), and a 4-residue cytoplasmic tail. A cleavage at the membrane-proximal external region by the tumor necrosis factor-α converting enzyme (TACE) releases the shed GP. The first 295 residues of ssGP, sGP, and GP are common, but each protein has a different C-terminus, leading to different functions. (B) Epitope masking by EBOV glycoproteins. Molecular surface of EBOV GP subunits (PDB code: 3CSY) are shown in green (GP1) and yellow (GP2). Complex-type N-linked glycans are modeled onto the EBOV GP surface as red/white spheres to reveal a heavy glycan layer that buries much of the GP surface, including the receptor-binding site; only a small patch at the base of the GP is accessible (KZ52/16F6 antibody-binding site). The O-linked glycosylated mucin-like domain (blue) is modeled onto EBOV GP, and thought to form an extended structure that provides another glycan layer of protection to the virus. EBOV GP is estimated to be ∼150 Å in height. Given the size and shape of EBOV GP, smaller cellular surface proteins, such as MHC class I and β-integrins (∼70 Å in height), may be sterically blocked.
Figure 2.
Structural conservation of the viral glycoprotein immunomodulatory region.
The immunomodulatory region is approximately 20 amino acids long and is found within numerous retroviruses and filoviruses. In each case presented here, the experimentally defined immunomodulatory region is rendered in yellow and residues that are necessary for the observed immunomodulatory activity are depicted as spheres. (A) Head-on view of viral glycoproteins exhibiting a conserved three-fold pinwheel structure. (B) Side-view illustrating the differences in possible interaction faces between the lentiviral gp41 immunomodulatory region and a representative retrovirus, HTLV-1. The outward positioning of the important immunomodulatory residues shown for HTLV-1 gp21 can be observed in all available retroviral and filoviral post-fusion glycoprotein structures except SIV gp41. The PDB codes for the fusion glycoproteins are as follows: EBOV GP2, 2EBO; MARV GP2, 4G2K; HTLV-1 gp21, 1MG1; syncytin-2, 1Y4M; SIV gp41, 2EZO.