Role of protein N-glycosylation in pathogenesis of human immunodeficiency virus type 1.
Human immunodeficiency virus type 1 (HIV-1), the retrovirus responsible for acquired immunodeficiency syndrome (AIDS), contains two heavily glycosylated envelope proteins, gp120 and gp41, which mediate attachment of virions to glycosylated cell surface receptor molecules (CD4 antigens) and appear to be responsible for syncytium formation and associated cytopathic effects of this virus. A comprehensive study of the effects of N-linked glycoprotein processing inhibitors on HIV-1 replication, infectivity, cytopathicity, target-cell infectibility, syncytium formation, and gp120 electrophoretic mobility was conducted to assess the importance of protein glycosylation in the pathogenesis of HIV-1 in vitro. The electrophoretic mobility of gp120 was decreased when gp120 was synthesized in the presence of castanospermine or 1-deoxynojirimycin (inhibitors of glucosidase I), increased when gp120 was synthesized in the presence of 1-deoxymannojirimycin (mannosidase I) or swainsonine (mannosidase II), and unaffected when gp120 was synthesized in the presence of bromoconduritol (glucosidase II). Inhibition by tunicamycin (lipid-linked oligosaccharide precursor synthesis), castanospermine, 1-deoxynojirimycin, and 1-deoxymannojirimycin attenuated HIV-1 infectivity and blocked HIV-1-induced syncytium formation and cytopathicity, whereas bromoconduritol and swainsonine failed to have such effects. None of the inhibitors interfered with virus replication in acutely infected cells or affected the ability of target cells to form syncytia with untreated HIV-1-infected cells. These results demonstrate that protein N-glycosylation is critical to the pathogenesis of HIV-1 at the levels of viral infectivity and cytopathicity but not at the level of virus replication or of host-cell infectibility.
Montefiori
D C
DC
Department of Pathology, Vanderbilt University, School of Medicine, Nashville, TN 37232.
Robinson
W E
WE
Mitchell
W M
WM
D000163:Acquired Immunodeficiency Syndrome / Q000382:microbiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D006023:Glycoproteins / Q000032:analysis*; D006031:Glycosylation; D015497:HIV-1 / Q000032:analysis / Q000472:pathogenicity*; D006801:Humans; D008358:Mannose / Q000378:metabolism; D009844:Oligosaccharides / Q000032:analysis; D014759:Viral Envelope Proteins / Q000032:analysis*
D000945:Antigens, Differentiation, T-Lymphocyte; D006023:Glycoproteins; D009844:Oligosaccharides; D014759:Viral Envelope Proteins; D008358:Mannose