title: Gelsolin activity controls efficient early HIV-1 infection.
abstract: BACKGROUND
  HIV-1 entry into target lymphocytes requires the activity of actin adaptors that stabilize and reorganize cortical F-actin, like moesin and filamin-A. These alterations are necessary for the redistribution of CD4-CXCR4/CCR5 to one pole of the cell, a process that increases the probability of HIV-1 Envelope (Env)-CD4/co-receptor interactions and that generates the tension at the plasma membrane necessary to potentiate fusion pore formation, thereby favouring early HIV-1 infection. However, it remains unclear whether the dynamic processing of F-actin and the amount of cortical actin available during the initial virus-cell contact are required to such events.
  
  
  RESULTS
  Here we show that gelsolin restructures cortical F-actin during HIV-1 Env-gp120-mediated signalling, without affecting cell-surface expression of receptors or viral co-receptor signalling. Remarkably, efficient HIV-1 Env-mediated membrane fusion and infection of permissive lymphocytes were impaired when gelsolin was either overexpressed or silenced, which led to a loss or gain of cortical actin, respectively. Indeed, HIV-1 Env-gp120-induced F-actin reorganization and viral receptor capping were impaired under these experimental conditions. Moreover, gelsolin knockdown promoted HIV-1 Env-gp120-mediated aberrant pseudopodia formation. These perturbed-actin events are responsible for the inhibition of early HIV-1 infection.
  
  
  CONCLUSIONS
  For the first time we provide evidence that through its severing of cortical actin, and by controlling the amount of actin available for reorganization during HIV-1 Env-mediated viral fusion, entry and infection, gelsolin can constitute a barrier that restricts HIV-1 infection of CD4+ lymphocytes in a pre-fusion step. These findings provide important insights into the complex molecular and actin-associated dynamics events that underlie early viral infection. Thus, we propose that gelsolin is a new factor that can limit HIV-1 infection acting at a pre-fusion step, and accordingly, cell-signals that regulate gelsolin expression and/or its actin-severing activity may be crucial to combat HIV-1 infection.
authors.affiliation: Cellular and Viral Immunology Lab, Department of Physical Medicine and Pharmacology, School of Medicine, University of La Laguna, Campus de Ofra s/n, Tenerife 38071, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Expósito
authors.forename: Serena
authors.initials: S
authors.lastname: Ziglio
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barroso-González
authors.forename: Laura
authors.initials: L
authors.lastname: de Armas-Rillo
authors.forename: María-Soledad
authors.initials: MS
authors.lastname: Valera
authors.forename: Donato
authors.initials: D
authors.lastname: Zipeto
authors.forename: José-David
authors.initials: JD
authors.lastname: Machado
authors.forename: Agustín
authors.initials: A
authors.lastname: Valenzuela-Fernández
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors*; D000998:Antiviral Agents / Q000378:metabolism* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D018260:Gelsolin / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D015728:Receptors, HIV / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D053586:Virus Internalization
chemical_list: D000199:Actins; D000998:Antiviral Agents; D018260:Gelsolin; D015728:Receptors, HIV