Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2008 Mar 11

PMID 18329615

Citations 93

Authors

Hye-Sook Kwon

Michael M Brent

Ruth Getachew

Prerana Jayakumar

Lin-Feng Chen

Martina Schnolzer

Michael W McBurney

Ronen Marmorstein

Warner C Greene

Melanie Ott

Affiliations

Soon will be listed here.

Abstract

Symptoms of T cell hyperactivation shape the course and outcome of HIV-1 infection, but the mechanism(s) underlying this chronic immune activation are not well understood. We find that the viral transactivator Tat promotes hyperactivation of T cells by blocking the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of NF-kappaB. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-kappaB-responsive genes, a function lost in SIRT1-/- cells. These results support a model where the normal function of SIRT1 as a negative regulator of T cell activation is suppressed by Tat during HIV infection. These events likely contribute to the state of immune cell hyperactivation found in HIV-infected individuals.

Citing Articles

Viruses and the Brain-A Relationship Prone to Trouble.

Mielcarska M, Rouse B Viruses. 2025; 17(2).

PMID: 40006958 PMC: 11860391. DOI: 10.3390/v17020203.

HIV-1 Tat Protein and Cigarette Smoke Mediated ADAM17 Upregulation Can Lead to Impaired Mucociliary Clearance.

Panda K, Santiago M, Rahman M, Ghorai S, Black S, Rahman I Cells. 2024; 13(23).

PMID: 39682757 PMC: 11640087. DOI: 10.3390/cells13232009.

Multi-protomics analysis identified host cellular pathways perturbed by tick-borne encephalitis virus infection.

Sui L, Wang W, Guo X, Zhao Y, Tian T, Zhang J Nat Commun. 2024; 15(1):10435.

PMID: 39616195 PMC: 11608235. DOI: 10.1038/s41467-024-54628-w.

Altered Host microRNAomics in HIV Infections: Therapeutic Potentials and Limitations.

Santiago M, Chinnapaiyan S, Panda K, Rahman M, Ghorai S, Rahman I Int J Mol Sci. 2024; 25(16.

PMID: 39201495 PMC: 11354509. DOI: 10.3390/ijms25168809.

Combination antiretroviral therapy prevents SIV- induced aging in the hippocampus and neurodegeneration throughout the brain.

MacLean A, Horn M, Midkiff C, Van Zandt A, Saied A Res Sq. 2024; .

PMID: 39149452 PMC: 11326353. DOI: 10.21203/rs.3.rs-4681317/v1.

References

Dorr A, Kiermer V, Pedal A, Rackwitz H, Henklein P, Schubert U . Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. EMBO J. 2002; 21(11):2715-23. PMC: 125383. DOI: 10.1093/emboj/21.11.2715. View

Wei P, Garber M, Fang S, Fischer W, Jones K . A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell. 1998; 92(4):451-62. DOI: 10.1016/s0092-8674(00)80939-3. View

Blander G, Guarente L . The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004; 73:417-35. DOI: 10.1146/annurev.biochem.73.011303.073651. View

Baur J, Sinclair D . Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006; 5(6):493-506. DOI: 10.1038/nrd2060. View

Fenard D, Yonemoto W, de Noronha C, Cavrois M, Williams S, Greene W . Nef is physically recruited into the immunological synapse and potentiates T cell activation early after TCR engagement. J Immunol. 2005; 175(9):6050-7. DOI: 10.4049/jimmunol.175.9.6050. View

Mujtaba S, He Y, Zeng L, Farooq A, Carlson J, Ott M . Structural basis of lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain. Mol Cell. 2002; 9(3):575-86. DOI: 10.1016/s1097-2765(02)00483-5. View

Waldmann T . The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006; 6(8):595-601. DOI: 10.1038/nri1901. View

Kiernan R, Bres V, Ng R, El Messaoudi S, Sardet C, Jin D . Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J Biol Chem. 2002; 278(4):2758-66. DOI: 10.1074/jbc.M209572200. View

Westendorp M, Li-Weber M, FRANK R, Krammer P . Human immunodeficiency virus type 1 Tat upregulates interleukin-2 secretion in activated T cells. J Virol. 1994; 68(7):4177-85. PMC: 236340. DOI: 10.1128/JVI.68.7.4177-4185.1994. View

10.

Cota-Gomez A, Flores N, Cruz C, Casullo A, Aw T, Ichikawa H . The human immunodeficiency virus-1 Tat protein activates human umbilical vein endothelial cell E-selectin expression via an NF-kappa B-dependent mechanism. J Biol Chem. 2002; 277(17):14390-9. DOI: 10.1074/jbc.M108591200. View

11.

Li C, Ueda Y, Shi B, Borodyansky L, Huang L, Li Y . Tat protein induces self-perpetuating permissivity for productive HIV-1 infection. Proc Natl Acad Sci U S A. 1997; 94(15):8116-20. PMC: 21566. DOI: 10.1073/pnas.94.15.8116. View

12.

Garber M, Wei P, Kewalramani V, Mayall T, Herrmann C, Rice A . The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein. Genes Dev. 1998; 12(22):3512-27. PMC: 317238. DOI: 10.1101/gad.12.22.3512. View

13.

Wang J, Kiyokawa E, Verdin E, Trono D . The Nef protein of HIV-1 associates with rafts and primes T cells for activation. Proc Natl Acad Sci U S A. 2000; 97(1):394-9. PMC: 26674. DOI: 10.1073/pnas.97.1.394. View

14.

Scala G, Ruocco M, Ambrosino C, Mallardo M, Giordano V, Baldassarre F . The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. J Exp Med. 1994; 179(3):961-71. PMC: 2191426. DOI: 10.1084/jem.179.3.961. View

15.

Rice A, Carlotti F . Mutational analysis of the conserved cysteine-rich region of the human immunodeficiency virus type 1 Tat protein. J Virol. 1990; 64(4):1864-8. PMC: 249332. DOI: 10.1128/JVI.64.4.1864-1868.1990. View

16.

Barboric M, Nissen R, Kanazawa S, Jabrane-Ferrat N, Peterlin B . NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell. 2001; 8(2):327-37. DOI: 10.1016/s1097-2765(01)00314-8. View

17.

Chen L, Mu Y, Greene W . Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. EMBO J. 2002; 21(23):6539-48. PMC: 136963. DOI: 10.1093/emboj/cdf660. View

18.

Fortin J, Barat C, Beausejour Y, Barbeau B, Tremblay M . Hyper-responsiveness to stimulation of human immunodeficiency virus-infected CD4+ T cells requires Nef and Tat virus gene products and results from higher NFAT, NF-kappaB, and AP-1 induction. J Biol Chem. 2004; 279(38):39520-31. DOI: 10.1074/jbc.M407477200. View

19.

Lee Y, Eum S, Nath A, Toborek M . Estrogen-mediated protection against HIV Tat protein-induced inflammatory pathways in human vascular endothelial cells. Cardiovasc Res. 2004; 63(1):139-48. DOI: 10.1016/j.cardiores.2004.03.006. View

20.

Yeung F, Hoberg J, Ramsey C, Keller M, Jones D, Frye R . Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004; 23(12):2369-80. PMC: 423286. DOI: 10.1038/sj.emboj.7600244. View