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      HIV entry in macrophages is dependent on intact lipid rafts

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          Abstract

          Macrophages are an important natural target cell for HIV-1, but previous studies of virus entry into these cells are limited, and the involvement of membrane cholesterol and lipid rafts is unknown. Cholesterol disruption of macrophage membranes using four pharmacological agents acting by different mechanisms: methyl-β cyclodextrin, nystatin, filipin complex and Lovastatin, all significantly inhibited productive HIV entry and reverse transcription. The inhibitory effects of these drugs resulted in decreased virus release from infected cells, and could be substantially reversed by the addition of water-soluble cholesterol. The virus bound equally to cholesterol-disrupted cells even though HIV receptor expression levels were significantly reduced. Macrophage CD4 and CCR5 were found to partition with the detergent-resistant membranes with a typical raft-associating protein flotillin-1. HIV particles were observed co-localising with a marker of lipid rafts (CTB-FITC) early post infection. These data suggest that macrophage membrane cholesterol is essential for HIV entry, and implicate lipid raft involvement.

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          Most cited references59

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          Virus Entry: Open Sesame

          Detailed information about the replication cycle of viruses and their interactions with host organisms is required to develop strategies to stop them. Cell biology studies, live-cell imaging, and systems biology have started to illuminate the multiple and subtly different pathways that animal viruses use to enter host cells. These insights are revolutionizing our understanding of endocytosis and the movement of vesicles within cells. In addition, such insights reveal new targets for attacking viruses before they can usurp the host-cell machinery for replication.
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            A quantitative assay for HIV DNA integration in vivo.

            Early steps of infection by HIV-1 involve entry of the viral core into cells, reverse transcription to form the linear viral DNA, and integration of that DNA into a chromosome of the host. The unintegrated DNA can also follow non-productive pathways, in which it is circularized by recombination between DNA long-terminal repeats (LTRs), circularized by ligation of the DNA ends or degraded. Here we report quantitative methods that monitor formation of reverse transcription products, two-LTR circles and integrated proviruses. The integration assay employs a novel quantitative form of Alu-PCR that should be generally applicable to studies of integrating viruses and gene transfer vectors.
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              The HIV lipidome: a raft with an unusual composition.

              The lipids of enveloped viruses play critical roles in viral morphogenesis and infectivity. They are derived from the host membranes from which virus budding occurs, but the precise lipid composition has not been determined for any virus. Employing mass spectrometry, this study provides a quantitative analysis of the lipid constituents of HIV and a comprehensive comparison with its host membranes. Both a substantial enrichment of the unusual sphingolipid dihydrosphingomyelin and a loss of viral infectivity upon inhibition of sphingolipid biosynthesis in host cells are reported, establishing a critical role for this lipid class in the HIV replication cycle. Intriguingly, the overall lipid composition of native HIV membranes resembles detergent-resistant membrane microdomains and is strikingly different from that of host cell membranes. With this composition, the HIV lipidome provides strong evidence for the existence of lipid rafts in living cells.
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                Author and article information

                Contributors
                Journal
                Virology
                Virology
                Virology
                Academic Press
                0042-6822
                1096-0341
                30 January 2009
                30 March 2009
                30 January 2009
                : 386
                : 1
                : 192-202
                Affiliations
                Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
                Author notes
                [* ]Corresponding author. william.james@ 123456path.ox.ac.uk
                Article
                S0042-6822(08)00855-6
                10.1016/j.virol.2008.12.031
                7103383
                19185899
                ccd05683-5c11-486f-a672-003a65269635
                Copyright © 2008 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 31 October 2008
                : 18 November 2008
                : 22 December 2008
                Categories
                Article

                Microbiology & Virology
                hiv,macrophages,cholesterol,entry,lipid rafts
                Microbiology & Virology
                hiv, macrophages, cholesterol, entry, lipid rafts

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