Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India.
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
PLoS One. 2018 Mar 26;13(3):e0194498. doi: 10.1371/journal.pone.0194498. eCollection 2018.
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.
靶向 HIV-1 包膜（Env）糖蛋白表面 N-聚糖的凝集素具有作为抗病毒药物的潜力。尽管在解析凝集素与 Env 聚糖相互作用的分子细节方面已经取得了进展，但仍需要进一步的研究来更好地了解 HIV-1 分离株中 Env 聚糖的异质性及其对病毒中和敏感性的影响。本研究评估了一组具有精细特异性的凝集素，用于检测不同的寡糖，并评估它们抑制已知对 HIV-Env 抗体敏感性不同的 HIV-1 病毒感染的能力。结果表明，HIV-1 分离株对特异性结合α1-3Man、α1-6Man 和α1-2Man 的凝集素有不同的敏感性。考虑到凝集素专门识别病毒 Env 的寡糖成分，这些数据表明 HIV-1 分离株之间的聚糖异质性可能解释了这种差异敏感性。为了进一步评估这一点，在存在不同糖苷酶抑制剂的情况下产生慢性和急性病毒，以表达更同质的聚糖。富含α1-2Man 终止 Man5-9GlcNAc2 聚糖的病毒对α1-2Man 结合凝集素变得同样敏感。α1-3Man-和α1-6Man-结合凝集素对主要表达 Man5GlcNAc2 和末端具有α1-3Man 和α1-6Man 的杂合型聚糖的病毒也更有效。此外，甘露聚糖竞争性缓解了凝集素介导的抑制作用，并且这种作用通过病毒上甘露糖型聚糖的富集而增强。此外，虽然富含甘露糖型聚糖的病毒的 Env 对 Endo-H 糖苷酶处理敏感，但未经处理的病毒的 Env 部分抵抗，表明 HIV-1 Env 聚糖是由复杂的、杂合的和甘露糖型组成的异质聚糖。总体而言，我们的数据表明 HIV-1 分离株对凝集素有不同的敏感性，部分原因是病毒 Env 糖蛋白表面表达的 N-连接聚糖的微异质性。
