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.
Argyris
Elias G
EG
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.
Acheampong
Edward
E
Nunnari
Giuseppe
G
Mukhtar
Muhammad
M
Williams
Kevin Jon
KJ
Pomerantz
Roger J
RJ
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