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MBC in Press, published online ahead of print September 7, 2005
Mol. Biol. Cell 10.1091/mbc.E05-04-0354

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Submitted on April 26, 2005
Revised on August 22, 2005
Accepted on August 29, 2005

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

Monitoring Editor: Ralph Isberg

Efficient HIV-1 infection depends on multiple interactions between the viral gp41/gp120 envelope 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 lymphocyte 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, knock down 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.

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




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