The HIV glycan shield as a target for broadly neutralizing antibodies

Abstract

The HIV envelope glycoprotein (Env) is the sole target for HIV broadly neutralizing antibodies (bnAbs). HIV Env is one of the most heavily glycosylated proteins known, with approximately half of its mass consisting of host-derived N-linked glycans. The high density of glycans creates a shield that impedes antibody recognition but, critically, some of the most potent and broadly active bnAbs have evolved to recognize epitopes formed by these glycans. Although the virus hijacks the host protein synthesis and glycosylation machinery to generate glycosylated HIV Env, studies have shown that HIV Env glycosylation diverges from that typically observed on host-derived glycoproteins. In particular, the high density of glycans leads to a nonself motif of underprocessed oligomannose-type glycans that forms the target of some of the most broad and potent HIV bnAbs. This review discusses the changing perception of the HIV glycan shield, and summarizes the protein-directed and cell-directed factors controlling HIV Env glycosylation that impact on HIV bnAb recognition and HIV vaccine design strategies.

Keywords: HIV; broadly neutralizing antibody; envelope trimer; glycosylation; vaccine.

Figure 1

The mannose patch consists of microclusters of glycans. (A) Model of the glycosylated HIV Env trimer 40 based on the recent structures of BG505 SOSIP.664 31, 58, 59 viewed from the trimer apex. The N‐linked glycans are shown in green, and the protein in grey. Glycans are modelled as high‐mannose. (B) Glycan modelling showing examples of direct glycan–glycan stabilization between N386 and N392 (shown in orange), and long‐range glycan–glycan stabilization between N488 and N332 mediated through interaction with glycan N295 (shown in blue).

Figure 2

Both protein‐directed and cell‐directed effects determine the glycosylation of HIV Env. The gp160 precursor is glycosylated in the ER at glycosylation sequons NXT/S (where X can be any amino acid except proline) with oligomannose‐type glycans. As gp160 moves through the Golgi compartments, the glycoprotein is exposed to glycan‐processing enzymes, which convert oligomannose‐type glycans (green) into complex‐type glycans (grey). The dense clustering of glycans on the gp120 outer domain limits the accessibility of the ER mannosidase I enzyme, leading to a patch of unprocessed oligomannose‐type glycans (referred to as the mannose patch), which is present on all forms of HIV Env, including recombinant monomeric gp120. The quaternary and compact structure of native trimeric HIV Env, as revealed by the EM images, further restricts the accessibility of processing enzymes, resulting in the secreted protein having a predominant oligomannose population. Uncleaved HIV Env trimer has a more open structure, as observed on the EM images. This allows easier access of the glycan‐processing enzymes, and a larger population of the oligomannose glycans are therefore processed to complex‐type glycans. The glycans on gp41 are not restricted in the same way as on gp120, and complex‐type glycan structures therefore predominate. This figure is adapted from 45.