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Review
. 2020 Apr 8;27(4):507-518.
doi: 10.1016/j.chom.2020.03.018.

Env Exceptionalism: Why Are HIV-1 Env Glycoproteins Atypical Immunogens?

P J Klasse  1 , Gabriel Ozorowski  2 , Rogier W Sanders  3 , John P Moore  4
Affiliations
Review

Env Exceptionalism: Why Are HIV-1 Env Glycoproteins Atypical Immunogens?

P J Klasse et al. Cell Host Microbe. .

Abstract

Recombinant HIV-1 envelope (Env) glycoproteins of ever-increasing sophistication have been evaluated as vaccine candidates for over 30 years. Structurally defined mimics of native trimeric Env glycoproteins (e.g., SOSIP trimers) present multiple epitopes for broadly neutralizing antibodies (bNAbs) and their germline precursors, but elicitation of bNAbs remains elusive. Here, we argue that the interactions between Env and the immune system render it exceptional among viral vaccine antigens and hinder its immunogenicity in absolute and comparative terms. In other words, Env binds to CD4 on key immune cells and transduces signals that can compromise their function. Moreover, the extensive array of oligomannose glycans on Env shields peptidic B cell epitopes, impedes the presentation of T helper cell epitopes, and attracts mannose binding proteins, which could affect the antibody response. We suggest lines of research for assessing how to overcome obstacles that the exceptional features of Env impose on the creation of a successful HIV-1 vaccine.

Keywords: CD4; HIV-1; HIV-1 Env trimers; adaptive immunity; envelope glycoprotein; innate immunity; mannose glycans; nanoparticles; neutralizing Abs; vaccine.

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Figures

Figure 1.
Figure 1.. HIV-1 Env is a highly glycosylated, metastable trimer of heterodimers.
(A) The linear polypeptide map highlights the gp120 and gp41 subunits, constant and variable regions (C and V), and the engineered sequence changes conferring stability to recombinant HIV-1 Env SOSIP.664 trimers. The site on the precursor for cleavage by furin in the Golgi is marked; RRRRRR is a motif for enhance cleavage; FP=fusion peptide; HR=heptad repeat region; CC=disulfide bonded loop in gp41; MPER=membrane-proximate external region; TM=transmembrane region; CTD=cytoplasmic domain. (B) Structural comparison of HIV-1 Env (a gp120 subunit and the SOSIP.664 trimer), the influenza hemagglutinin (HA) and the RSV F glycoprotein. Peptidic surfaces are shown in grey and idealized oligomannose (Man-9) N-linked glycans as green spheres. The CD4bs of HIV-1 Env is highlighted in purple. The top view (upper row) is defined as looking down towards the viral membrane. The models are based on PDB 6mco, 4o5n and 6q0s.
Figure 2.
Figure 2.. Icosahedral nanoparticle display of HIV-1 Env SOSIP.664 trimers.
The entire nanoparticle with 20 HIV-1 Env SOSIP trimers distributed in icosahedral symmetry is shown to the left with idealized N-linked glycans in green, peptidic Env surfaces in grey, and the non-Env components in blue. To the right a magnified trimer with its non-Env scaffold component is shown with the same color code (Brouwer et al., 2019). The model is based on PDB 6p6f and EMD-20261.
Figure 3.
Figure 3.. Presumed MBL interacting surface on HIV-1 Env.
The approximate areas of MBL interaction with terminal mannose residues on an HIV-1 Env SOSIP.664 trimer are indicated on two protomers as orange ellipses; the third is hidden from view. The area extends over the gp120-gp41 interface from the CD4bs site towards the trimer base. The model is based on data obtained from a competition ELISA with MBL and bNAbs (Ringe et al., 2020).
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