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Originally published as MBC in Press, 10.1091/mbc.E05-04-0354 on September 7, 2005

Vol. 16, Issue 11, 5445-5454, November 2005

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Histone Deacetylase 6 Regulates Human Immunodeficiency Virus Type 1 Infection

Agustín Valenzuela-Fernández *, Susana Álvarez {dagger}, Mónica Gordon-Alonso *, Marta Barrero *, Ángeles Ursa *, J. Román Cabrero *, Gerónimo Fernández {dagger}, Salvador Naranjo-Suárez *, Maria Yáñez-Mo *, Juan M. Serrador *, M. Ángeles Muñoz-Fernández {dagger}, and Francisco Sánchez-Madrid *

* Servicio de Inmunología, Hospital Universitario de La Princesa, 28006 Madrid, Spain; {dagger} Departamento de Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain

Submitted April 26, 2005; Revised August 22, 2005; Accepted August 29, 2005
Monitoring Editor: Ralph Isberg

Efficient human immunodeficiency virus (HIV)-1 infection depends on multiple interactions between the viral gp41/gp120 envelope (Env) proteins and cell surface receptors. However, cytoskeleton-associated proteins that modify membrane dynamics may also regulate the formation of the HIV-mediated fusion pore and hence viral infection. Because the effects of HDAC6-tubulin deacetylase on cortical {alpha}-tubulin regulate cell migration and immune synapse organization, we explored the possible role of HDAC6 in HIV-1-envelope-mediated cell fusion and infection. The binding of the gp120 protein to CD4+-permissive cells increased the level of acetylated {alpha}-tubulin in a CD4-dependent manner. Furthermore, overexpression of active HDAC6 inhibited the acetylation of {alpha}-tubulin, and remarkably, prevented HIV-1 envelope-dependent cell fusion and infection without affecting the expression and codistribution of HIV-1 receptors. In contrast, knockdown of HDAC6 expression or inhibition of its tubulin deacetylase activity strongly enhanced HIV-1 infection and syncytia formation. These results demonstrate that HDAC6 plays a significant role in regulating HIV-1 infection and Env-mediated syncytia formation.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-04-0354) on September 7, 2005.

Abbreviations used: HDAC6, histone deacetylase 6; NaBut, sodium butyrate; PBL, peripheral blood lymphocyte; siRNA, short interference RNA; TSA, trichostatin A.

Address correspondence to: F. Sánchez-Madrid (fsanchez.hlpr{at}salud.madrid.org).




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