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

Yuyang Tang, Ihid Carneiro Leao, Ebony M. Coleman, Robin Shepard Broughton, James E K Hildreth

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 virustransformed 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.

    Original languageEnglish (US)
    Pages (from-to)7982-7995
    Number of pages14
    JournalJournal of Virology
    Volume83
    Issue number16
    DOIs
    StatePublished - Aug 2009

    ASJC Scopus subject areas

    • Immunology
    • Virology

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