Histone deacetylase 6 regulates human immunodeficiency virus type 1 infection.

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.

[1]  F. Sánchez‐Madrid,et al.  Involvement of the CD4 molecule in a post‐activation event on T cell proliferation , 1987, European journal of immunology.

[2]  G. Piperno,et al.  Microtubules containing acetylated alpha-tubulin in mammalian cells in culture , 1987, The Journal of cell biology.

[3]  Edgar G. Engleman,et al.  pH-independent HIV entry into CD4-positive T cells via virus envelope fusion to the plasma membrane , 1987, Cell.

[4]  R. Axel,et al.  HIV infection does not require endocytosis of its receptor, CD4 , 1988, Cell.

[5]  M. Marsh,et al.  Human immunodeficiency virus infection of CD4‐bearing cells occurs by a pH‐independent mechanism. , 1988, The EMBO journal.

[6]  J. Spouge,et al.  HIV requires multiple gp120 molecules for CD4-mediated infection , 1990, Nature.

[7]  D. Phillips,et al.  Role of the cytoskeleton in cell-to-cell transmission of human immunodeficiency virus , 1994, Journal of virology.

[8]  O. Danos,et al.  Impairment of T cell receptor-dependent stimulation in CD4+ lymphocytes after contact with membrane-bound HIV-1 envelope glycoprotein. , 1994, Virology.

[9]  S. Arya,et al.  Identification of RANTES, MIP-1α, and MIP-1β as the Major HIV-Suppressive Factors Produced by CD8+ T Cells , 1995, Science.

[10]  Ying Sun,et al.  The β-Chemokine Receptors CCR3 and CCR5 Facilitate Infection by Primary HIV-1 Isolates , 1996, Cell.

[11]  Paul E. Kennedy,et al.  HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor , 1996, Science.

[12]  C. Broder,et al.  CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. , 1996, Science.

[13]  J. Sodroski,et al.  The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry , 1996, Nature.

[14]  Virginia Litwin,et al.  HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 , 1996, Nature.

[15]  Marc Parmentier,et al.  A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors , 1996, Cell.

[16]  Stephen C. Peiper,et al.  Identification of a major co-receptor for primary isolates of HIV-1 , 1996, Nature.

[17]  C. Broder,et al.  CC CKR5: A RANTES, MIP-1α, MIP-1ॆ Receptor as a Fusion Cofactor for Macrophage-Tropic HIV-1 , 1996, Science.

[18]  A. Trkola,et al.  Co-receptors for HIV-1 entry. , 1997, Current opinion in immunology.

[19]  J. Blanco,et al.  Neutralizing antibodies against the V3 loop of human immunodeficiency virus type 1 gp120 block the CD4-dependent and -independent binding of virus to cells , 1997, Journal of virology.

[20]  N. Heveker,et al.  Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry. , 1997, Science.

[21]  M. Stevenson,et al.  Establishment of a Functional Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcription Complex Involves the Cytoskeleton , 1998, The Journal of experimental medicine.

[22]  C. Casale,et al.  Na+,K+-ATPase was found to be the membrane component responsible for the hydrophobic behavior of the brain membrane tubulin. , 1998, Biochemical and biophysical research communications.

[23]  David H. Schwartz,et al.  Actin-Dependent Receptor Colocalization Required for Human Immunodeficiency Virus Entry into Host Cells , 1998, Journal of Virology.

[24]  S. Schreiber,et al.  Three proteins define a class of human histone deacetylases related to yeast Hda1p. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  C. Broder,et al.  A mechanism of resistance to HIV-1 entry: inefficient interactions of CXCR4 with CD4 and gp120 in macrophages. , 1999, Virology.

[26]  E. Salmon,et al.  Positive feedback interactions between microtubule and actin dynamics during cell motility. , 1999, Current opinion in cell biology.

[27]  Irina Kaverina,et al.  Microtubule Targeting of Substrate Contacts Promotes Their Relaxation and Dissociation , 1999, The Journal of cell biology.

[28]  P Wadsworth,et al.  Regional regulation of microtubule dynamics in polarized, motile cells. , 1999, Cell motility and the cytoskeleton.

[29]  R. Blumenthal,et al.  Varying effects of temperature, Ca2+ and cytochalasin on fusion activity mediated by human immunodeficiency virus type 1 and type 2 glycoproteins , 2000, FEBS letters.

[30]  R. Doms.  Beyond receptor expression: the influence of receptor conformation, density, and affinity in HIV-1 infection. , 2000, Virology.

[31]  L. Tsai,et al.  Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1 , 2000, Nature Cell Biology.

[32]  R. Doms,et al.  The plasma membrane as a combat zone in the HIV battlefield. , 2000, Genes & development.

[33]  C. Broder,et al.  Inefficient formation of a complex among CXCR4, CD4 and gp120 in U937 clones resistant to X4 gp120-gp41-mediated fusion. , 2000, Experimental and molecular pathology.

[34]  Minoru Yoshida,et al.  Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm , 2000, Current Biology.

[35]  J. Galzi,et al.  Optimal Inhibition of X4 HIV Isolates by the CXC Chemokine Stromal Cell-derived Factor 1α Requires Interaction with Cell Surface Heparan Sulfate Proteoglycans* , 2001, The Journal of Biological Chemistry.

[36]  S. Horinouchi,et al.  In vivo destabilization of dynamic microtubules by HDAC6‐mediated deacetylation , 2002, The EMBO journal.

[37]  Á. McKnight,et al.  Cell surface receptors, virus entry and tropism of primate lentiviruses. , 2002, The Journal of general virology.

[38]  Manuel A. González,et al.  Single‐step, multiple retroviral transduction of human T cells , 2002, The journal of gene medicine.

[39]  Ben Berkhout,et al.  Synergistic Activation of Human Immunodeficiency Virus Type 1 Promoter Activity by NF-κB and Inhibitors of Deacetylases: Potential Perspectives for the Development of Therapeutic Strategies , 2002, Journal of Virology.

[40]  Yuqi Zhao,et al.  Quantification of Human Immunodeficiency Virus Type 1 Proviral DNA by Using TaqMan Technology , 2002, Journal of Clinical Microbiology.

[41]  Lucas Pelkmans,et al.  Local Actin Polymerization and Dynamin Recruitment in SV40-Induced Internalization of Caveolae , 2002, Science.

[42]  Xiao-Fan Wang,et al.  HDAC6 is a microtubule-associated deacetylase , 2002, Nature.

[43]  P. Matthias,et al.  HDAC‐6 interacts with and deacetylates tubulin and microtubules in vivo , 2003, The EMBO journal.

[44]  C. Casale,et al.  Involvement of acetylated tubulin in the regulation of Na+,K+‐ATPase activity in cultured astrocytes , 2003, FEBS letters.

[45]  Stuart L Schreiber,et al.  Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  E. Clercq.  The bicyclam AMD3100 story , 2003, Nature Reviews Drug Discovery.

[47]  B. Sodeik,et al.  Herpes simplex virus type 1 infection of polarized epithelial cells requires microtubules and access to receptors present at cell-cell contact sites. , 2004, The Journal of general virology.

[48]  N. Bertos,et al.  Role of the Tetradecapeptide Repeat Domain of Human Histone Deacetylase 6 in Cytoplasmic Retention* , 2004, Journal of Biological Chemistry.

[49]  F. Sánchez‐Madrid,et al.  HDAC6 deacetylase activity links the tubulin cytoskeleton with immune synapse organization. , 2004, Immunity.

[50]  Clare Jolly,et al.  HIV-1 Cell to Cell Transfer across an Env-induced, Actin-dependent Synapse , 2004, The Journal of experimental medicine.

[51]  H. Barra,et al.  Conversion of hydrophilic tubulin into a hydrophobic compound. Evidence for the involvement of membrane proteins , 1997, Molecular and Cellular Biochemistry.

[52]  G. Kroemer,et al.  Mechanisms of apoptosis induction by the HIV-1 envelope , 2005, Cell Death and Differentiation.

[53]  Minoru Yoshida,et al.  HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. , 2005, Molecular cell.

[54]  F. Saltel,et al.  A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts , 2005, Journal of Cell Science.

[55]  S. Schreiber,et al.  Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer , 2005, Oncogene.