Histone Deacetylase 6 Regulates Human Immunodeficiency Virus Type 1 Infection

Abstract

Efficient human immunodeficiency virus (HIV)-1 infection depends on multiple interactions between the viral gp41/gp120envelope (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 ␣-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 ␣-tubulin in a CD4-dependent manner. Furthermore, overexpression of active HDAC6 inhibited the acetylation of ␣-tubulin, and remarkably, prevented HIV-1 envelopedependent 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. INTRODUCTIONHuman immunodeficiency virus (HIV) infection is initiated by the virus binding to the cell surface after CD4 engagement and HIV-1 fusion with the plasma membrane (Stein et al., 1987;Maddon et al., 1988;McClure et al., 1988;Moore et al., 1997). The main coreceptors for HIV-1 infection have been shown to be CXCR4 and CCR5, which represented a major advance in understanding the mechanism of the HIV-1 infection (Cocchi et al., 1995;Alkhatib et al., 1996;Bleul et al., 1996;Choe et al., 1996;Deng et al., 1996;Doranz et al., 1996;Dragic et al., 1996;Feng et al., 1996). As a result, it has been proposed that the sequential binding of gp120 viral protein to CD4 and to one coreceptor induces specific conformational changes in gp41, facilitating viral fusion with cell membrane (Clapham and McKnight, 2002).The cell cytoskeleton is involved in the early events of viral infection, regulating viral penetration and genome uncoating, the movement of viral capsids, and integration of the viral genome. Accordingly, actin and microtubules are required for the efficient entry of herpes simplex type 1 and simian virus 40, respectively (Pelkmans et al., 2002;Marozin et al., 2004). It has been shown that disrupting the actin network can inhibit infection of HIV-1 and fusion with the host cell (Iyengar et al., 1998;Jernigan et al., 2000), presumably by disrupting the colocalization of CD4 and CXCR4 (Iyengar et al., 1998). In addition, the actin cytoskeleton seems to be necessary for activation of the reverse transcription complex (Bukrinskaya et al., 1998). However, little is known about the role of cytoskeleton-related enzymes in the control of HIV fusion and infection.Histone deacetylase 6 (HDAC6) is exclusively located in the cytoplasm, and it regulates the acetylation of ␣-tubulin (Hubbert et al., 2002;Matsuyama et al., 2002;Haggarty et al., 2003;Z...

Tetraspanins CD9 and CD81 Modulate HIV-1-Induced Membrane Fusion

“…Then, the subcellular localization of CD81 and CD4 was studied in T lymphocytes exposed to HIV-1 and during syncytia formation. We found that in CEM 1.3 cells and T lymphoblasts exposed to HIV-1 virions, CD4 and CD81 were concentrated at the area of viral contact, a phenomena called capping (38,42) (Fig. 1C and data not shown).…”

“…HIV-1 NL4.3 entry and infection were assayed in HeLa P5 cells as described previously (38). Briefly, HIV-1 NL4.3 infection of HeLa P5 cells was conducted in 96-well plates for 5 h at 37°C.…”

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

“…Indeed, cytoskeleton-dependent functions of HDAC6 have been shown to be crucial in HIV-1 infection of CD4 þ cells. An HDAC6-dependent increase in tubulin acetylation occurs following HIV-1 Env-CD4 receptor interaction in the CD4 þ cells, which could be an important event in HIV-1 cell fusion and infection (Valenzuela-Fernandez et al, 2005). Accordingly, HDAC6 downregulation or the inhibition of its catalytic activity by a specific drug significantly stimulates HIV-1 infection (Valenzuela-Fernandez et al, 2005).…”

Infection with Replication-deficient Adenovirus Induces Changes in the Dynamic Instability of Host Cell Microtubules

“…HDAC6 also has important roles in some viral infections. The internalization of human immunodeficiency virus (HIV) is regulated by HDAC6, and its overexpression and subsequent deacetylation of MTs inhibited the HIV infection process (Valenzuela-Fernandez et al, 2005). ASFV viral replication factories distinctly resemble aggresomes (Heath et al, 2001), and as such it is possible that manipulation of HDAC6, not changes in MT stability, leads to the hyperacetylation of MTs after ASFV infection.…”