BackgroundCholesterol 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.ResultsWe 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.ConclusionsThese results suggest cholesterol trafficking and localization can profoundly affect HIV-1 infectivity by modulating the cholesterol content of the virions.
HIV‐1infection induces formation of a virological synapse wherein CD4, chemokine receptors, and cell adhesion moleculessuch as the integrin LFA‐1 [RNSB1]form localized domains on the cell surface. Previous studies have shown that LFA‐1 on the surface of HIV‐1 particlesnot only retains its cellular function but also enhances virus attachment to susceptible cells by binding its counterreceptor ICAM‐1. Findings from our laboratory revealed that monoclonal antibodies (Mab) specific for LFA‐1 blocked HIV‐1 mediated syncytia formationand enhanced neutralization by antibodies from AIDS patients and by gp120 Mabs. The objective of this study is to determine if LFA‐1/ICAM‐1 interaction plays a limiting role in apoptosis, a process linked to both HIV‐1 infection and integrin biology such that disruption of this interaction leads to increasedapoptosis in HIV‐1‐infected cells. Using the TUNEL assay, we observed increased cell death in HIV‐1‐infected primary T cells treated with anti‐LFA‐1 Mab[RNSB2], as well as increased caspase 8 activation. HIV‐1‐infected cells treated with anti‐LFA‐1 Mab also released less virus compared to HIV‐1‐infected cells alone. These results suggests that anti‐LFA‐1 Mab blocks HIV‐1 infection by inducing apoptosis and that LFA‐1‐mediated signaling may be necessary to prevent HIV‐1‐induced apoptosis, thereby contributing to the spread of infection.Supported by NIH (R01HD040772)
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