The “glycan shield” exposed on the surface of the HIV-1 gp120 env glycoprotein has been previously proposed as a novel target for anti-HIV treatments. While such targeting of these glycans provides an exciting prospect for HIV treatment, little is known about the conservation and variability of glycosylation patterns within and between the various HIV-1 group M subtypes and circulating recombinant forms. Here, we present evidence of strong strain-specific glycosylation patterns and show that the epitope for the 2G12 neutralising antibody is poorly conserved across HIV-1 group M. The unique glycosylation patterns within the HIV-1 group M subtypes and CRFs appear to explain their varying susceptibility to neutralisation by broadly cross-neutralising (BCN) antibodies. Compensatory glycosylation at linearly distant yet three-dimensionally proximal amino acid positions appears to maintain the integrity of the glycan shield while conveying resistance to neutralisation by BCN antibodies. We find that highly conserved clusters of glycosylated residues do exist on the gp120 trimer surface and suggest that these positions may provide an exciting target for the development of BCN anticarbohydrate therapies. 1. Introduction The envelope gene of human immunodeficiency virus type 1 (HIV-1) encodes a gp160 precursor that is cleaved to form gp120 and gp41 that exists as a trimer on the surface of a HIV virion and is responsible for host cell recognition and binding. As the envelope protein moves through the endoplasmic reticulum, N-linked glycans are added to aid correct folding and processing of the protein [1–3]. The gp120 protein is one of the most heavily known glycosylated proteins [3–5]. The carbohydrates present on gp120 are created by the host cell and, as such, are recognised as immunologically “self” by the host immune system. Studies have shown that the “glycan shield” bound to gp120 can prevent neutralisation of the virus by antibodies [6–13]. It has been suggested that lowly glycosylated viruses may be replicatively fitter and are thus selected early on in infection with glycosylated viruses only being selected for following the activation of the host humoral immune response [14–18]. This trend does not occur in all cases; however, it has been suggested that it occurs more frequently in particular viral subtypes [17, 19]. Domains on gp120 responsible for receptor binding and trimer interactions tend to exhibit low levels of glycosylation resulting in the designation of three domains within gp120: the neutralizing face, the nonneutralizing face, and the
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