Glycosphingolipid composition of human immunodeficiency virus type 1 (HIV-1) particles is a crucial determinant for dendritic cell-mediated HIV-1 trans-infection.
Interactions of human immunodeficiency virus type 1 (HIV-1) with dendritic cells (DCs) are multifactorial and presumably require nonredundant interactions between the HIV-1 envelope glycoprotein gp120 and molecules expressed on the DC surface that define the cellular fate of the virus particle. Surprisingly, neutralization of HIV-1 gp120-dependent binding interactions with DCs was insufficient to prevent HIV-1 attachment. Besides gp120, HIV-1 particles also incorporate host cell-derived proteins and lipids in their particle membrane. In this study, we demonstrate a crucial role for host cell-derived glycosphingolipids (GSLs) for the initial interactions of HIV-1 particles with both immature and mature DCs. Production of HIV-1 particles from virus producer cells treated with ceramide synthase inhibitor fumonisin B1 or glucosylceramide synthase inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) resulted in the production of virus particles that, although capable of binding previously defined HIV-1 gp120-specific attachment factors CD4, DC-SIGN, and syndecans, were attenuated in their ability to be captured by both immature and mature DCs. Furthermore, GSL-deficient HIV-1 particles were inhibited in their ability to establish productive infections in DC-T-cell cocultures. These studies provide initial evidence for the role of HIV-1 particle membrane-associated GSLs in virus invasion of DCs and also provide additional novel cellular targets, GSL biosynthetic pathways and GSL-dependent HIV-1 interactions with DCs, for development of antiviral therapy.
Hatch
Steven C
SC
Department of Microbiology, Boston University School of Medicine, 72 E. Concord St., R509, Boston, MA 02118, USA.
Archer
Jacob
J
Gummuluru
Suryaram
S
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000821:virology*; D004791:Enzyme Inhibitors; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006028:Glycosphingolipids / Q000032:analysis*; D015497:HIV-1 / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D053585:Virus Attachment; D053586:Virus Internalization
D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase