Skip to main content

Advertisement

SpringerLink
Log in

Increased expression of BCL11B and its recruited chromatin remodeling factors during highly active antiretroviral therapy synergistically represses the transcription of human immunodeficiency virus type 1 and is associated with residual immune activation

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Persistence of human immunodeficiency virus 1 (HIV-1) latency and residual immune activation remain major barriers to treatment in patients receiving highly active antiretroviral therapy (HAART). In the present study, we investigated the molecular mechanisms of persistent HIV infection and residual immune activation in HAART-treated patients. We showed that the expression level of B-cell CLL/lymphoma 11B (BCL11B) was significantly increased in CD4+T cells from HIV-infected patients undergoing HAART, and this was accompanied by increased expression of BCL11B-associated chromatin modifiers and inflammatory factors in comparison to healthy controls and untreated patients with HIV. In vitro assays showed that BCL11B significantly inhibited HIV-1 long terminal repeat (LTR)-mediated transcription. Knockdown of BCL11B resulted in the activation of HIV latent cells, and dissociation of BCL11B and its related chromatin remodeling factors from the HIV LTR. Our findings suggested that increased expression of BCL11B and its related chromatin modifiers contribute to HIV-1 transcriptional silencing, and alteration of BCL11B levels might lead to abnormal transcription and inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Tyagi M, Bukrinsky M (2012) Human immunodeficiency virus (HIV) latency: the major hurdle in HIV eradication. Mol Med 18:1096–1108

    Article  CAS  Google Scholar 

  2. Paiardini M, Muller-Trutwin M (2013) HIV-associated chronic immune activation. Immunol Rev 254:78–101

    Article  Google Scholar 

  3. Mousseau G, Valente ST (2017) Role of host factors on the regulation of Tat-mediated HIV-1 transcription. Curr Pharm Des 23:4079–4090

    Article  CAS  Google Scholar 

  4. Avram D, Fields A, Top KPO, Nevrivy DJ, Ishmael JE, Leid M (2000) Isolation of a novel family of C2H2 zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors. J Biol Chem 275:10315–10322

    Article  CAS  Google Scholar 

  5. Cysique LA, Juge L, Lennon MJ, Gates TM, Jones SP, Lovelace MD, Rae CD, Johnson TP, Nath A, Brew BJ (2019) HIV brain latency as measured by CSF Bcl11b relates to disrupted brain cellular energy in virally suppressed HIV infection. AIDS 33:433–441

    Article  CAS  Google Scholar 

  6. Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, Ellis R, Cherner M, Grant I, Masliah E (2013) Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 80:1415–1423

    Article  CAS  Google Scholar 

  7. Cismasiu VB, Paskaleva E, Suman Daya S, Canki M, Duus K, Avram D (2008) BCL11B is a general transcriptional repressor of the HIV-1 long terminal repeat in T lymphocytes through recruitment of the NuRD complex. Virology 380:173–181

    Article  CAS  Google Scholar 

  8. Avram D, Fields A, Senawong T, Topark-Ngarm A, Leid M (2002) COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein. Biochem J 368:555–563

    Article  CAS  Google Scholar 

  9. Shaim H, Estrov Z, Harris D, Hernandez SM, Liu Z, Ruvolo P, Thompson PA, Ferrajoli A, Daher M, Burger J, Muftuoglu M, Imahashi N, Li L, Liu E, Alsuliman AS, Basar R, Nassif KL, Sobieski C, Gokdemir E, Kondo K, Wierda W, Keating M, Shpall EJ, Rezvani K (2017) The CXCR4-STAT3-IL-10 pathway controls the immunoregulatory function of chronic lymphocytic leukemia and is modulated by lenalidomide. Front Immunol 8:1773

    Article  Google Scholar 

  10. Zhou Y, Chen H, Liu L, Yu X, Sukhova GK, Yang M, Zhang L, Kyttaris VC, Tsokos GC, Stillman IE, Ichimura T, Bonventre JV, Libby P, Shi GP (2017) CD74 deficiency mitigates systemic lupus erythematosus-like autoimmunity and pathological findings in mice. J Immunol 198:2568–2577

    Article  CAS  Google Scholar 

  11. Fang M, Xu N, Shao X, Yang J, Wu N, Yao H (2012) Inhibitory effects of human immunodeficiency virus gp120 and Tat on CpG-A-induced inflammatory cytokines in plasmacytoid dendritic cells. Acta Biochim Biophys Sin (Shanghai) 44:797–804

    Article  CAS  Google Scholar 

  12. Shou C, Weng N, Jin Y, Feng L, Jin C, Hoextermann S, Potthoff A, Skaletz-Rorowski A, Brockmeyer NH, Wu N (2011) Study of T cell subsets and IL-7 protein expression in HIV-1-infected patients after 7 years HAART. Eur J Med Res 16:473–479

    Article  CAS  Google Scholar 

  13. Jordan A, Bisgrove D, Verdin E (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J 22:1868–1877

    Article  CAS  Google Scholar 

  14. Spandidos A, Wang X, Wang H, Seed B (2009) PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res 38:D792–D799

    Article  Google Scholar 

  15. Marban C, Redel L, Suzanne S, Van Lint C, Lecestre D, Chasserot-Golaz S, Leid M, Aunis D, Schaeffer E, Rohr O (2005) COUP-TF interacting protein 2 represses the initial phase of HIV-1 gene transcription in human microglial cells. Nucleic Acids Res 33:2318–2331

    Article  CAS  Google Scholar 

  16. Marban C, Suzanne S, Dequiedt F, de Walque S, Redel L, Van Lint C, Aunis D, Rohr O (2007) Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J 26:412–423

    Article  CAS  Google Scholar 

  17. Bader J, Daumer M, Schoni-Affolter F, Boni J, Gorgievski-Hrisoho M, Martinetti G, Thielen A, Klimkait T (2017) Therapeutic immune recovery and reduction of CXCR4-tropic HIV-1. Clin Infect Dis 64:295–300

    Article  CAS  Google Scholar 

  18. Hamlyn E, Hickling S, Porter K, Frater J, Phillips R, Robinson M, Mackie NE, Kaye S, McClure M, Fidler S (2012) Increased levels of CD4 T-cell activation in individuals with CXCR4 using viruses in primary HIV-1 infection. AIDS 26:887–890

    Article  CAS  Google Scholar 

  19. Weinberger AD, Perelson AS (2011) Persistence and emergence of X4 virus in HIV infection. Math Biosci Eng 8:605–626

    Article  Google Scholar 

  20. Le Noury DA, Mosebi S, Papathanasopoulos MA, Hewer R (2015) Functional roles of HIV-1 Vpu and CD74: Details and implications of the Vpu-CD74 interaction. Cell Immunol 298:25–32

    Article  Google Scholar 

  21. Jones RB (2019) Current challenges and recent advances in the search for a cure for HIV. J Int Aids Soc 22:e25248

    Article  Google Scholar 

  22. Nasi M, Pinti M, Mussini C, Cossarizza A (2014) Persistent inflammation in HIV infection: established concepts, new perspectives. Immunol Lett 161:184–188

    Article  CAS  Google Scholar 

  23. Cote SC, Stilla A, Burke SS, Berthoud TK, Angel JB (2019) IL-7-induced proliferation of peripheral Th17 cells is impaired in HAART-controlled HIV infection. AIDS 33:985–991

    Article  CAS  Google Scholar 

  24. Cismasiu VB, Ghanta S, Duque J, Albu DI, Chen HM, Kasturi R, Avram D (2006) BCL11B participates in the activation of IL2 gene expression in CD4 + T lymphocytes. Blood 108:2695–2702

    Article  CAS  Google Scholar 

  25. Lennon MJ, Jones SP, Lovelace MD, Guillemin GJ, Brew BJ (2017) Bcl11b-A critical neurodevelopmental transcription factor-roles in health and disease. Front Cell Nurosci 11:89

    Google Scholar 

  26. Sun J, Chen H, Xie Y, Su J, Huang Y, Xu L, Yin M, Zhou Q, Zhu B (2017) Nuclear factor of activated T cells and cytokines gene expression of the T cells in AIDS patients with immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. Mediat Inflamm 2017:1754741

    Google Scholar 

  27. Bogoi RN, de Pablo A, Valencia E, Martin-Carbonero L, Moreno V, Vilchez-Rueda HH, Asensi V, Rodriguez R, Toledano V, Rodes B (2018) Expression profiling of chromatin-modifying enzymes and global DNA methylation in CD4 + T cells from patients with chronic HIV infection at different HIV control and progression states. Clin Epigenet 10:20

    Article  Google Scholar 

  28. Raurell-Vila H, Bosch-Presegue L, Gonzalez J, Kane-Goldsmith N, Casal C, Brown JP, Marazuela-Duque A, Singh PB, Serrano L, Vaquero A (2017) An HP1 isoform-specific feedback mechanism regulates Suv39h1 activity under stress conditions. Epigenet US 12:166–175

    Article  Google Scholar 

  29. Shirai A, Kawaguchi T, Shimojo H, Muramatsu D, Ishida-Yonetani M, Nishimura Y, Kimura H, Nakayama JI, Shinkai Y (2017) Impact of nucleic acid and methylated H3K9 binding activities of Suv39h1 on its heterochromatin assembly. Elife 6:e25317

    Article  Google Scholar 

  30. Lue H, Dewor M, Leng L, Bucala R, Bernhagen J (2011) Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74. Cell Signal 23:135–144

    Article  CAS  Google Scholar 

  31. Su H, Na N, Zhang X, Zhao Y (2017) The biological function and significance of CD74 in immune diseases. Inflamm Res 66:209–216

    Article  CAS  Google Scholar 

  32. Mo XM, Sun HX (2015) The anti-inflammatory effect of the CXCR4 antagonist-N15P peptide and its modulation on inflammation-associated mediators in LPS-Induced PBMC. Inflammation 38:1374–1383

    Article  CAS  Google Scholar 

  33. Wada NI, Jacobson LP, Margolick JB, Breen EC, Macatangay B, Penugonda S, Martínez-Maza O, Bream JH (2015) The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation. AIDS 29:463–471

    Article  CAS  Google Scholar 

  34. de Paula H, Ferreira A, Caetano DG, Delatorre E, Teixeira S, Coelho LE, Joao EG, de Andrade MM, Cardoso SW, Grinsztejn B, Veloso VG, Morgado MG, Guimaraes ML, Cortes FH (2018) Reduction of inflammation and T cell activation after 6 months of cART initiation during acute, but not in early chronic HIV-1 infection. Retrovirology 15:76

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Natural Science Funds of Zhejiang Province (Grant no. LQ19H100002), the Medical and Health Science and Technology Planning Project of Zhejiang Province (2017KY275), the Public Technology Research/Social Development Program of Zhejiang Province (no. LGF19H190003), the Hangzhou Science and Technology Development Program (no. 20150733Q50)

Author information

Author notes

  1. Nan-Ping Wu and Jin Yang contributed equally to this work

Authors and Affiliations

  1. Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People’s Republic of China

    Juan Wang

  2. The Second Department of Infectious Disease, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang, People’s Republic of China

    Zongxing Yang

  3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People’s Republic of China

    Nan-Ping Wu

  4. Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, Zhejiang, People’s Republic of China

    Jin Yang

Authors
  1. Juan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zongxing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan-Ping Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nan-Ping Wu or Jin Yang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest. All subjects who participated in this study provided written informed consent. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University.

Additional information

Handling Editor: Li Wu.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Yang, Z., Wu, NP. et al. Increased expression of BCL11B and its recruited chromatin remodeling factors during highly active antiretroviral therapy synergistically represses the transcription of human immunodeficiency virus type 1 and is associated with residual immune activation. Arch Virol 165, 321–330 (2020). https://doi.org/10.1007/s00705-019-04475-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-019-04475-8

Search

Navigation