Abstract
ABSTRACTThe HIV envelope glycoprotein (Env) is extensively modified with host-derived N-linked glycans. The high density of glycosylation on the viral spike limits enzymatic processing, resulting in numerous underprocessed oligomannose-type glycans. This extensive glycosylation not only shields conserved regions of the protein from the immune system but also acts as a target for anti-HIV broadly neutralizing antibodies (bnAbs). In response to the host immune system, the HIV glycan shield is constantly evolving through mutations affecting both the positions and numbers of potential N-linked glycosylation sites (PNGSs). Here, using longitudinal Env sequences from a clade C-infected individual (CAP256), we measured the impact of the shifting glycan shield during HIV infection on the abundance of oligomannose-type glycans. By analyzing the intrinsic mannose patch from a panel of recombinant CAP256 gp120s displaying high protein sequence variability and changes in PNGS number and positioning, we show that the intrinsic mannose patch persists throughout the course of HIV infection and correlates with the number of PNGSs. This effect of the glycan density on the processing state was also supported by the analysis of a cross-clade panel of recombinant gp120 glycoproteins. Together, these observations underscore the importance of glycan clustering for the generation of carbohydrate epitopes for anti-HIV bnAbs. The persistence of the intrinsic mannose patch over the course of HIV infection further highlights this epitope as an important target for HIV vaccine strategies.IMPORTANCE Development of an HIV vaccine is critical for control of the HIV pandemic, and elicitation of broadly neutralizing antibodies (bnAbs) is likely to be a key component of a successful vaccine response. The HIV envelope glycoprotein (Env) is covered in an array of host-derived N-linked glycans often referred to as the glycan shield. This glycan shield is a target for many of the recently isolated anti-HIV bnAbs and is therefore under constant pressure from the host immune system, leading to changes in both glycan site frequency and location. This study aimed to determine whether these genetic changes impacted the eventual processing of glycans on the HIV Env and the susceptibility of the virus to neutralization. We show that despite this variation in glycan site positioning and frequency over the course of HIV infection, the mannose patch is a conserved feature throughout, making it a stable target for HIV vaccine design.
Highlights
The HIV envelope glycoprotein (Env) is extensively modified with host-derived N-linked glycans
In the CAP256 donor, there was a general trend toward increasing numbers of potential N-linked glycosylation sites (PNGSs) early in infection that decreased at the latest time point, which is consistent with previous studies [44, 45]
As the glycan shield is a dynamic entity that is under constant pressure from the host immune system, we looked for correlations over shorter periods to reflect this
Summary
The HIV envelope glycoprotein (Env) is extensively modified with host-derived N-linked glycans. The high density of glycosylation on the viral spike limits enzymatic processing, resulting in numerous underprocessed oligomannose-type glycans This extensive glycosylation shields conserved regions of the protein from the immune system and acts as a target for antiHIV broadly neutralizing antibodies (bnAbs). The HIV envelope glycoprotein (Env) is covered in an array of host-derived N-linked glycans often referred to as the glycan shield This glycan shield is a target for many of the recently isolated anti-HIV bnAbs and is under constant pressure from the host immune system, leading to changes in both glycan site frequency and location. HIV Env is under constant pressure from the host immune system, in particular neutralizing antibodies, and as such, the location and frequency of PNGSs often change [3, 34] This observation has led to the concept of the shifting or evolving glycan shield [3]. Removal of the N276 glycan has been shown to confer sensitivity to germ line variants of CD4 binding site bnAbs, e.g., VRC01 and NIH45-46, indicating that addition of this glycan as a potential escape mechanism is critical for development of a broadly neutralizing CD4 binding site antibody response [38]
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