Human immunodeficiency virus type 1 enters primary human brain microvascular endothelial cells by a mechanism involving cell surface proteoglycans independent of lipid rafts.
Several studies have reported a crucial role for cholesterol-enriched membrane lipid rafts and cell-associated heparan sulfate proteoglycans (HSPGs), a class of molecules that can localize in lipid rafts, in the entry of human immunodeficiency virus type 1 (HIV-1) into permissive cells. For the present study, we examined the role of these cell surface moieties in HIV-1 entry into primary human brain microvascular endothelial cells (BMVECs), which represent an important HIV-1 central nervous system-based cell reservoir and a portal for neuroinvasion. Cellular cholesterol was depleted by exposure to beta-cyclodextrins and 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase inhibitors (statins), the loss of cholesterol was quantitated, and disruption of membrane rafts was verified by immunofluorescence. Nevertheless, these treatments did not affect binding of several strains of HIV-1 virions to BMVECs at 4 degrees C or their infectivities at 37 degrees C. In contrast, we confirmed that cholesterol depletion and raft disruption strongly inhibited HIV-1 binding and infection of Jurkat T cells. Enzymatic digestion of cell-associated HSPGs on human BMVECs dramatically inhibited HIV-1 infection, and our data from quantitative HIV-1 DNA PCR analysis strongly suggest that cell-associated chondroitin sulfate proteoglycans greatly facilitate infective entry of HIV-1 into human BMVECs. These findings, in combination with our earlier work showing that human BMVECs lack CD4, indicate that the molecular mechanisms for HIV-1 entry into BMVECs are fundamentally different from that of viral entry into T cells, in which lipid rafts, CD4, and probably HSPGs play important roles.
The Dorrance H. Hamilton Laboratories, Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Elias G
EG
Argyris
Edward
E
Acheampong
Giuseppe
G
Nunnari
Muhammad
M
Mukhtar
Kevin Jon
KJ
Williams
Roger J
RJ
Pomerantz
D001921:Brain / Q000098:blood supply* / Q000821:virology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology; D011508:Chondroitin Sulfate Proteoglycans / Q000502:physiology; D042783:Endothelial Cells / Q000821:virology*; D004730:Endothelium, Vascular / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006493:Heparin / Q000031:analogs & derivatives* / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000502:physiology*; D008833:Microcirculation; D011509:Proteoglycans / Q000502:physiology*
D011508:Chondroitin Sulfate Proteoglycans; D011509:Proteoglycans; C036090:heparin proteoglycan; D006493:Heparin; D002784:Cholesterol