title: Cell-to-cell contact facilitates HIV transmission from lymphocytes to astrocytes via CXCR4.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Guan-Han
authors.initials: GH
authors.lastname: Li
authors.forename: Caroline
authors.initials: C
authors.lastname: Anderson
authors.forename: Laura
authors.initials: L
authors.lastname: Jaeger
authors.forename: Thao
authors.initials: T
authors.lastname: Do
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D001253:Astrocytes / Q000821:virology*; D002459:Cell Fusion; D002478:Cells, Cultured; D003584:Cytological Techniques; D006678:HIV / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000821:virology*; D008853:Microscopy; D019718:Receptors, CXCR4 / Q000378:metabolism*; D053586:Virus Internalization; D057074:Virus Release
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4