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Cell-to-cell contact facilitates HIV transmission from lymphocytes to astrocytes via CXCR4

Li, Guan-Hana; Anderson, Carolinea; Jaeger, Lauraa; Do, Thaob; Major, Eugene O.c; Nath, Avindraa

doi: 10.1097/QAD.0000000000000605
Basic Science

Objectives: HIV reservoir in the brain represents a major barrier for curing HIV infection. As the most abundant, long-lived cell type, astrocytes play a critical role in maintaining the reservoir; however, the mechanism of infection remains unknown. Here, we determine how viral transmission occurs from HIV-infected lymphocytes to astrocytes by cell-to-cell contact.

Design and methods: Human astrocytes were exposed to HIV-infected lymphocytes and monitored by live-imaging, confocal microscopy, transmission and three-dimensional electron microscopy. A panel of receptor antagonists was used to determine the mechanism of viral entry.

Results: We found that cell-to-cell contact resulted in efficient transmission of X4 or X4R5-using viruses from T lymphocytes to astrocytes. In co-cultures of astrocytes with HIV-infected lymphocytes, the interaction occurred through a dynamic process of attachment and detachment of the two cell types. Infected lymphocytes invaginated into astrocytes or the contacts occurred via filopodial extensions from either cell type, leading to the formation of virological synapses. In the synapses, budding of immature or incomplete HIV particles from lymphocytes occurred directly onto the membranes of astrocytes. This cell-to-cell transmission could be almost completely blocked by anti-CXCR4 antibody and its antagonist, but only partially inhibited by anti-CD4, ICAM1 antibodies.

Conclusion: Cell-to-cell transmission was mediated by a unique mechanism by which immature viral particles initiated a fusion process in a CXCR4-dependent, CD4-independent manner. These observations have important implications for developing approaches to prevent formation of HIV reservoirs in the brain.

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aSection of Infections of the Nervous System, National Institute of Neurological Diseases and Stroke

bLaboratory of Cell Biology, Center for Cancer Research, National Cancer Institute

cLaboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Correspondence to Avindra Nath, Bldg 10, 7C-103, 10 Center Drive, Bethesda, MD 20892, USA. E-mail: natha@ninds.nih.gov

Received 14 November, 2014

Revised 24 January, 2015

Accepted 27 January, 2015

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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