期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 45, 页码 27345-27359出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.681338
关键词
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资金
- National Institutes of Health [P41GM10349010, HL107151]
- Robert Koch-Institute
- Sonnenfeld-Stiftung Berlin
- Spanish Secretariat for Research Grant [SAF2013-49042-R]
- Goethe University
- ICREA Funding Source: Custom
Background: Human Siglec-1 mediates HIV trans-infection by interaction with virion-associated sialylated gangliosides. Results: Here, Siglec-1 on mouse macrophages mediated trans-infection of surface-bound MLV. This could be inhibited by biosynthetic modification of sialic acids' N-acyl side chain in virus-producer cells. Conclusion: The N-acyl side chain is a critical determinant of Siglec-1-dependent MLV trans-infection. Significance: Glycoengineering allows manipulation of sialic acid-dependent virus/receptor interactions. Siglec-1 (sialoadhesin, CD169) is a surface receptor on human cells that mediates trans-enhancement of HIV-1 infection through recognition of sialic acid moieties in virus membrane gangliosides. Here, we demonstrate that mouse Siglec-1, expressed on the surface of primary macrophages in an interferon-alpha -responsive manner, captures murine leukemia virus (MLV) particles and mediates their transfer to proliferating lymphocytes. The MLV infection of primary B-cells was markedly more efficient than that of primary T-cells. The major structural protein of MLV particles, Gag, frequently co-localized with Siglec-1, and trans-infection, primarily of surface-bound MLV particles, efficiently occurred. To explore the role of sialic acid for MLV trans-infection at a submolecular level, we analyzed the potential of six sialic acid precursor analogs to modulate the sialylated ganglioside-dependent interaction of MLV particles with Siglec-1. Biosynthetically engineered sialic acids were detected in both the glycolipid and glycoprotein fractions of MLV producer cells. MLV released from cells carrying N-acyl-modified sialic acids displayed strikingly different capacities for Siglec-1-mediated capture and trans-infection; N-butanoyl, N-isobutanoyl, N-glycolyl, or N-pentanoyl side chain modifications resulted in up to 92 and 80% reduction of virus particle capture and trans-infection, respectively, whereas N-propanoyl or N-cyclopropylcarbamyl side chains had no effect. In agreement with these functional analyses, molecular modeling indicated reduced binding affinities for non-functional N-acyl modifications. Thus, Siglec-1 is a key receptor for macrophage/lymphocyte trans-infection of surface-bound virions, and the N-acyl side chain of sialic acid is a critical determinant for the Siglec-1/MLV interaction.
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