Abstract
Lectins that target N-glycans on the surface of HIV-1 envelope (Env) glycoprotein have the potential for use as antiviral agents. Although progress has been made in deciphering the molecular details of lectin and Env glycan interaction, further studies are needed to better understand Env glycan heterogeneity among HIV-1 isolates and its influence on virus-neutralization sensitivity to lectins. This study evaluated a panel of lectins with fine specificity for distinct oligosaccharides and assessed their ability to inhibit infection of HIV-1 viruses known to have differing sensitivity to anti-HIV Env antibodies. The results showed that HIV-1 isolates have different sensitivity to lectins specific for α1-3Man, α1-6Man, and α1-2Man binding lectins. Considering that lectins exclusively recognize the oligosaccharide components of virus Env, these data suggest that glycan heterogeneity among HIV-1 isolates may explain this differential sensitivity. To evaluate this further, chronic and acute viruses were produced in the presence of different glycosidase inhibitors to express more homogenous glycans. Viruses enriched for α1-2Man terminating Man5-9GlcNAc2 glycans became similarly sensitive to α1-2Man-binding lectins. The α1-3Man- and α1-6Man-binding lectins also were more potent against viruses expressing predominantly Man5GlcNAc2 and hybrid type glycans with terminal α1-3Man and α1-6Man. Furthermore, lectin-mediated inhibition was competitively alleviated by mannan and this effect was augmented by enrichment of mannose-type glycans on the virus. In addition, while Env of viruses enriched with mannose-type glycans were sensitive to Endo-H deglycosylation, Env of untreated viruses were partially resistant, indicating that HIV-1 Env glycans are heterogeneously comprised of complex, hybrid, and mannose types. Overall, our data demonstrate that HIV-1 isolates display differential sensitivity to lectins, in part due to the microheterogeneity of N-linked glycans expressed on the surface of the virus Env glycoprotein.
Highlights
With nearly 2 million new HIV-1 infections each year, the development of an HIV-1 vaccine remains a top public health priority
We found that HIV-1 strains displayed differences in sensitivity to lectins (Table 2), similar to that seen with antibodies, with tier 1 viruses more sensitive to lectins than were tier 2 viruses
We focused primarily on how glycan heterogeneity or differences in patterns of N-linked glycans on HIV-1 envelope glycoprotein (Env) glycoprotein determine the sensitivity of viruses to lectinmediated inhibition
Summary
With nearly 2 million new HIV-1 infections each year, the development of an HIV-1 vaccine remains a top public health priority. The glycan shield contributes approximately 50% of Env molecular mass, covering most of the Env surface While these glycans mask the conserved neutralizing antibody epitopes on HIV-1 Env [1, 7, 8], they can be targeted by broadly neutralizing antibodies (bnAbs) that are generated in a fraction of HIV-1-infected individuals after many years of infection [9, 10]. The majority of recently isolated bnAbs have been shown to recognize glycan-bearing epitopes [8, 11,12,13] These bnAbs are attractive anti-HIV-1 agents for passive transfer therapy, but their activity is influenced by the types of glycans expressed by the virus Env [13,14,15]. Evidence is accumulating that Env N-glycan composition controls virus capture by dendritic cells via C-type lectin receptors, which affects whether virus is degraded for antigen presentation or transmitted to CD4 T cells [29,30,31]
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