Infectivities of human and other primate lentiviruses are activated by desialylation of the virion surface.
The envelope protein, gp120, of human immunodeficiency virus type 1 (HIV-1) is heavily glycosylated and sialylated. The heavy sialylation greatly affects the physical properties of the protein, as it resolves into a wide acidic pH range despite the basic pI value predicted for its polypeptide backbone (B. S. Stein and E. G. Engleman, J. Biol. Chem. 265:2640-2649, 1990). However, the functional significance of the heavy sialylation remains elusive. Here, we show that desialylation of HIV-1 with neuraminidase greatly augments the initial virus-cell interaction, leading to remarkably enhanced viral replication and cytopathogenicity. This enhancement appeared to be a direct result of the removal of negatively charged sialic acids but not of the exposure of galactose residues or complement activation. Complementing these results, studies with inhibitors of mannosidase I and mannosidase II showed that the processing of HIV-1 oligosaccharides into the complex type to acquire the terminal sialic acid residues impeded the full replication capacity of the virus and that its prevention also enhanced virus replication and cytopathogenicity. Enhancement of infection by desialylation was found widely, with HIV-1 laboratory strains of different cell tropisms and primary isolates as well as HIV-2 and simian immunodeficiency virus. Thus, the sialylation catalyzed by host cell pathways appeared to reduce the infectivity of human and nonhuman primate lentiviruses. Our results further suggested that desialylation would help increase the titers of HIV-based vectors.
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Department of Viral Infection, Institute of Medical Science, University of Tokyo, Minato-ku, Japan.
Shioda
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T
Moriya
C
C
Xin
X
X
Hasan
M K
MK
Miyake
K
K
Shimada
T
T
Nagai
Y
Y
D017485:1-Deoxynojirimycin / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D016086:Lentivirus; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / Q000494:pharmacology; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D009439:Neuraminidase / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D014771:Virion; D014779:Virus Replication
D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C036137:2-deoxy-2,3-dehydro-N-acetylneuraminic acid; D006026:Glycoside Hydrolases; D009439:Neuraminidase; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; D019158:N-Acetylneuraminic Acid