ArticlePLoS pathogens2021
Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 22 citations in OpenAlex.
- Natural killer cells against viral infection: from basic biology to immunotherapy.Precision clinical medicine · 2026Review
- HIV-induced sialoglycans on infected CD4+ T cells promote immune evasion from myeloid cell-mediated killing.Nature communications · 2025Article
- A role for Fas/FasL-dependent NK-mediated cytotoxicity in infants with perinatal HIV.iScience · 2025Article
- Increase of Inhibitory Siglec receptors on T cells mitigates severe immune reactions during acute viral infections.PNAS nexus · 2025Article
- Interplay between innate immune cells and inflammatory mediators in dengue infection: an evolving therapeutic paradigm.Expert reviews in molecular medicine · 2025Review
- Balancing Host Defense and Viral Tolerance for the Development of Next-Generation Broad-Spectrum Antiviral Agents.Pathogens (Basel, Switzerland) · 2025Review
- NK-cell receptor modulation in viral infections.Clinical and experimental immunology · 2024Review
- ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer.Communications biology · 2024Article
- Uncloaking the viral glycocalyx: How do viruses exploit glycoimmune checkpoints?Advances in virus research · 2024Review
- Role of Siglecs in viral infections: A double-edged sword interaction.Molecular aspects of medicine · 2023Review
- Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2.mBio · 2023Article
- Mapping the interplay between NK cells and HIV: therapeutic implications.Journal of leukocyte biology · 2023Review
- Mucosal-homing natural killer cells are associated with aging in persons living with HIV.Cell reports. Medicine · 2022Article
- Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin.Frontiers in immunology · 2022Review
Corrections and comments
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Authors and funding
17 authors at 5 institutions in 1 country.
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Abstract
Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9+ CD56dim NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim NK cells inversely correlate with viral load during viremic infection and CD4+ T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9- NK cells. These data are consistent with the notion that Siglec-9+ NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells' ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9+ NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells' capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells' ability to evade NK immunosurveillance and developed an approach to break this interaction.
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