期刊
RETROVIROLOGY
卷 10, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1742-4690-10-39
关键词
Gelsolin; Actin-severing activity; Perturbed-actin dynamics and receptors clustering; Inhibition of early HIV-1 infection
类别
资金
- European Regional Development Fund
- Ministerio de Ciencia e Innovacion, Spain [SAF 2008-01729, 2011-24671]
- RIS-RETICS [RD12/0017/0034]
- Fundacion para la Investigacion y la Prevencion del SIDA en Espana (FIPSE), Spain [24661/07, 24-0740-09]
- Agencia Canaria de Investigacion, Innovacion y Sociedad de la Informacion, Canary Island Government, Spain [ProID20100020]
- SAF [2011-24671, 2008-01729]
- FPI
- University of Verona (Italy)
- University of La Laguna (Spain)
- Direccion General de Farmacia y Productos Sanitarios, Ministerio de Sanidad y Politica Social [EC11-043]
- Spanish Ramon & Cajal programme [RYC-2010-06256]
- [FIPSE-24-0740-09]
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.
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