Adsorptive endocytosis mediates the passage of HIV-1 across the blood-brain barrier: evidence for a post-internalization coreceptor.
HIV-1 induces the AIDS dementia complex and infects brain endothelial and glial cells. Because the endothelial cells comprising the blood-brain barrier (BBB) do not possess CD4 receptors or galactosylceramide binding sites, it is unclear how HIV-1 negotiates the BBB. Previous work has suggested that gp120, the glycoprotein viral coat of HIV-1, is capable of inducing adsorptive endocytosis. Glycoprotein lectins like wheatgerm agglutinin induce adsorptive endocytosis and greatly potentiate the uptake by and passage across mouse endothelial cells in vivo and in vitro. We show here that the wheatgerm agglutinin-induced binding of gp120 is dose-dependent and involves components of the cytoskeleton. The uptake is partially dependent on temperature and energy and is modestly enhanced by potassium depletion. Glycosylation of gp120 is critical for its uptake by adsorptive endocytosis since the non-glycosylated form of gp120 is unaffected by wheatgerm agglutinin. Evidence is presented for the existence of a coreceptor sensitive to protamine sulfate that is primarily involved in membrane fusion after 125I-gp120 has bound to the cell membrane and is probably activated after internalization. This coreceptor probably contains a negatively charged heparin sulfate group and could be a member of the chemokine receptor family.
Banks
W A
WA
Veterans Affairs Medical Center and Tulane Univeristy School of Medicine, New Orleans, LA 70146, USA. bbbpts@mailhost.tcs.tulane.edu
Akerstrom
V
V
Kastin
A J
AJ
D000327:Adsorption; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002462:Cell Membrane / Q000821:virology; D003599:Cytoskeleton / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D005947:Glucose; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011107:Polylysine / Q000494:pharmacology; D011188:Potassium / Q000502:physiology; D011479:Protamines / Q000494:pharmacology; D015728:Receptors, HIV / Q000378:metabolism*; D013696:Temperature; D014909:Wheat Germ Agglutinins / Q000494:pharmacology
D015699:HIV Envelope Protein gp120; D011479:Protamines; D015728:Receptors, HIV; D014909:Wheat Germ Agglutinins; D011107:Polylysine; D005947:Glucose; D011188:Potassium