HIV-1 Glycan Density Drives the Persistence of the Mannose Patch within an Infected Individual.
2016
ABSTRACT 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 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
glycanshield is constantly evolving through mutations affecting both the positions and numbers of potential
N-linked glycosylationsites (PNGSs). Here, using longitudinal Env sequences from a clade C-infected individual (CAP256), we measured the impact of the shifting
glycanshield during HIV infection on the abundance of oligomannose-type
glycans. By analyzing the intrinsic
mannosepatch from a panel of recombinant CAP256 gp120s displaying high protein sequence variability and changes in PNGS number and positioning, we show that the intrinsic
mannosepatch persists throughout the course of HIV infection and correlates with the number of PNGSs. This effect of the
glycandensity on the
processing statewas also supported by the analysis of a cross-clade panel of recombinant gp120 glycoproteins. Together, these observations underscore the importance of
glycanclustering for the generation of carbohydrate epitopes for anti-HIV bnAbs. The persistence of the intrinsic
mannosepatch over the course of HIV infection further highlights this epitope as an important target for
HIV vaccinestrategies. IMPORTANCE Development of an
HIV vaccineis 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
glycansoften referred to as the
glycanshield. This
glycanshield 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
glycansite frequency and location. This study aimed to determine whether these genetic changes impacted the eventual processing of
glycanson the HIV Env and the susceptibility of the virus to neutralization. We show that despite this variation in
glycansite positioning and frequency over the course of HIV infection, the
mannosepatch is a conserved feature throughout, making it a stable target for
HIV vaccinedesign.
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