title: Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes.
abstract: BACKGROUND
  Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. Here, we investigated the role of cholesterol trafficking in HIV-1 replication utilizing Niemann-Pick Type C disease (NPCD) cells as a model system.
  
  
  RESULTS
  We used a unique NPC2-deficient cell line (NPCD55) that exhibited Gag accumulation as well as decreased NPC1 expression after HIV infection. Virus release efficiency from NPCD55 cells was similar to that from control cells. However, we observed a 3 to 4-fold enhancement in the infectivity of virus released from these cells. Fluorescence microscopy revealed accumulation and co-localization of Gag proteins with cholesterol in late endosomal/lysosomal (LE/L) compartments of these cells. Virion-associated cholesterol was 4-fold higher in virions produced in NPCD55 cells relative to virus produced in control cells. Treatment of infected NPCD55 cells with the cholesterol efflux-inducing drug TO-9013171 reduced virus infectivity to control levels.
  
  
  CONCLUSIONS
  These results suggest cholesterol trafficking and localization can profoundly affect HIV-1 infectivity by modulating the cholesterol content of the virions.
authors.affiliation: Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN, USA.
authors.forename: Ebony M
authors.initials: EM
authors.lastname: Coleman
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Walker
authors.forename: James E K
authors.initials: JE
authors.lastname: Hildreth
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism* / Q000821:virology*; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry* / Q000254:growth & development / Q000472:pathogenicity; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins; D014771:Virion / Q000737:chemistry; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D002784:Cholesterol