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Journal of Virology, August 2009, p. 7982-7995, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00259-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Deficiency of Niemann-Pick Type C-1 Protein Impairs Release of Human Immunodeficiency Virus Type 1 and Results in Gag Accumulation in Late Endosomal/Lysosomal Compartments{triangledown}

Yuyang Tang,1,# Ihid Carneiro Leao,2,# Ebony M. Coleman,1 Robin Shepard Broughton,1 and James E. K. Hildreth1,2*

Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, Tennessee 37208,1 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 212052

Received 4 February 2009/ Accepted 20 May 2009

Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells. In the present study, we examine the need for intracellular cholesterol trafficking pathways with respect to HIV-1 biogenesis using Niemann-Pick type C-1 (NPC1)-deficient (NPCD) cells, wherein these pathways are severely compromised, causing massive accumulation of cholesterol in late endosomal/lysosomal (LE/L) compartments. We have found that induction of an NPC disease-like phenotype through treatment of various cell types with the commonly used hydrophobic amine drug U18666A resulted in profound suppression of HIV-1 release. Further, NPCD Epstein-Barr virus-transformed B lymphocytes and fibroblasts from patients with NPC disease infected with a CD4-independent strain of HIV-1 or transfected with an HIV-1 proviral clone, respectively, replicated HIV-1 poorly compared to normal cells. Infection of the NPCD fibroblasts with a vesicular stomatitis virus G-pseudotyped strain of HIV-1 produced similar results, suggesting a postentry block to HIV-1 replication in these cells. Examination of these cells using confocal microscopy showed an accumulation and stabilization of Gag in LE/L compartments. Additionally, normal HIV-1 production could be restored in NPCD cells upon expression of a functional NPC1 protein, and overexpression of NPC1 increased HIV-1 release. Taken together, our findings demonstrate that intact intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.

* Corresponding author. Mailing address: Center for AIDS Health Disparities Research, George Hubbard Hospital, Rm. 5035, Meharry Medical College, 1005 DB Todd Blvd., Nashville, TN 37208. Phone: (615) 327-5890. Fax: (615) 327-6929. E-mail: jhildreth{at}mmc.edu

{triangledown} Published ahead of print on 27 May 2009.

# These authors contributed equally to this work.

Journal of Virology, August 2009, p. 7982-7995, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00259-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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