Abstract
The addition of asparagine (N)-linked polysaccharide chains (i.e., glycans) to the gp120 and gp41 glycoproteins of human immunodeficiency virus type 1 (HIV-1) envelope is not only required for correct protein folding, but also may provide protection against neutralizing antibodies as a “glycan shield.” As a result, strong host-specific selection is frequently associated with codon positions where nonsynonymous substitutions can create or disrupt potential N-linked glycosylation sites (PNGSs). Moreover, empirical data suggest that the individual contribution of PNGSs to the neutralization sensitivity or infectivity of HIV-1 may be critically dependent on the presence or absence of other PNGSs in the envelope sequence. Here we evaluate how glycan–glycan interactions have shaped the evolution of HIV-1 envelope sequences by analyzing the distribution of PNGSs in a large-sequence alignment. Using a “covarion”-type phylogenetic model, we find that the rates at which individual PNGSs are gained or lost vary significantly over time, suggesting that the selective advantage of having a PNGS may depend on the presence or absence of other PNGSs in the sequence. Consequently, we identify specific interactions between PNGSs in the alignment using a new paired-character phylogenetic model of evolution, and a Bayesian graphical model. Despite the fundamental differences between these two methods, several interactions are jointly identified by both. Mapping these interactions onto a structural model of HIV-1 gp120 reveals that negative (exclusive) interactions occur significantly more often between colocalized glycans, while positive (inclusive) interactions are restricted to more distant glycans. Our results imply that the adaptive repertoire of alternative configurations in the HIV-1 glycan shield is limited by functional interactions between the N-linked glycans. This represents a potential vulnerability of rapidly evolving HIV-1 populations that may provide useful glycan-based targets for neutralizing antibodies.
Highlights
Proteins are frequently modified during or after translation by the enzymatic attachment of polysaccharide chains to amino acid residues
The envelope of the human immunodeficiency virus type 1 (HIV-1), for example, becomes coated with so many glycans that the virus can become invisible to the protein-specific immune response of the host
We have analyzed HIV-1 envelope sequences to identify cases where the presence of one glycan was dependent on the presence or absence of another
Summary
Proteins are frequently modified during or after translation by the enzymatic attachment of polysaccharide chains (i.e., glycans) to amino acid residues. The addition of glycans to asparagine residues is known as N-linked glycosylation and occurs widely in eukaryotes and archaebacteria, but only rarely in prokaryotes [1]. Glycosylation by the host cell can strongly influence the folding, stability, and biological function of virus-encoded proteins [3,4,5]. The surface glycoprotein (gp120) of the human immunodeficiency virus type 1 (HIV-1) envelope, which represents the primary interface between the virus and the host environment, is one of the most heavily glycosylated proteins known to date, with nearly half of its molecular weight due to the addition of N-linked glycans [8]. N-linked glycans can sterically prevent neutralizing antibodies from accessing the antigenic polypeptide surface of the HIV-1 envelope, thereby protecting the virus from the humoral immune response with a ‘‘glycan shield’’ [11]. The relative contribution of the glycan shield to protection from neutralization in vivo remains unresolved [13]
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