Vpr Driving DNA Methylation Variation of CD4 + T Cells in HIV-1 Infection

Overview

Journal Virol J

Publisher Biomed Central

Specialty Microbiology

Date 2024 Apr 26

PMID 38671522

Authors

Peipei Wang

Zhuoyue Meng

Kai Deng

Zhiliang Gao

Jinfeng Cai

Affiliations

Soon will be listed here.

Abstract

Background: Despite the existence of available therapeutic interventions for HIV-1, this virus remains a significant global threat, leading to substantial morbidity and mortality. Within HIV-1-infected cells, the accessory viral protein r (Vpr) exerts control over diverse biological processes, including cell cycle progression, DNA repair, and apoptosis. The regulation of gene expression through DNA methylation plays a crucial role in physiological processes, exerting its influence without altering the underlying DNA sequence. However, a thorough examination of the impact of Vpr on DNA methylation in human CD4 + T cells has not been conducted.

Methods: In this study, we employed base-resolution whole-genome bisulfite sequencing (WGBS), real-time quantitative RCR and western blot to explore the effect of Vpr on DNA methylation of host cells under HIV-1 infection.

Results: We observed that HIV-1 infection leads to elevated levels of global DNA methylation in primary CD4 + T cells. Specifically, Vpr induces significant modifications in DNA methylation patterns, particularly affecting regions within promoters and gene bodies. These alterations notably influence genes related to immune-related pathways and olfactory receptor activity. Moreover, Vpr demonstrates a distinct ability to diminish the levels of methylation in histone genes.

Conclusions: These findings emphasize the significant involvement of Vpr in regulating transcription through the modulation of DNA methylation patterns. Together, the results of this investigation will considerably enhance our understanding of the influence of HIV-1 Vpr on the DNA methylation of host cells, offer potential avenues for the development of more effective treatments.

References

Arumugam T, Ramphal U, Adimulam T, Chinniah R, Ramsuran V . Deciphering DNA Methylation in HIV Infection. Front Immunol. 2021; 12:795121. PMC: 8674454. DOI: 10.3389/fimmu.2021.795121. View

Wang Q, Su L . Vpr Enhances HIV-1 Env Processing and Virion Infectivity in Macrophages by Modulating TET2-Dependent IFITM3 Expression. mBio. 2019; 10(4). PMC: 6703422. DOI: 10.1128/mBio.01344-19. View

Shaknovich R, Cerchietti L, Tsikitas L, Kormaksson M, De S, Figueroa M . DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. Blood. 2011; 118(13):3559-69. PMC: 3186332. DOI: 10.1182/blood-2011-06-357996. View

Correa L, Jordan M, Carty S . DNA Methylation in T-Cell Development and Differentiation. Crit Rev Immunol. 2020; 40(2):135-156. PMC: 8048391. DOI: 10.1615/CritRevImmunol.2020033728. View

Lv L, Wang Q, Xu Y, Tsao L, Nakagawa T, Guo H . Vpr Targets TET2 for Degradation by CRL4 E3 Ligase to Sustain IL-6 Expression and Enhance HIV-1 Replication. Mol Cell. 2018; 70(5):961-970.e5. PMC: 6071318. DOI: 10.1016/j.molcel.2018.05.007. View

Luzzi A, Morettini F, Gazaneo S, Mundo L, Onnis A, Mannucci S . HIV-1 Tat induces DNMT over-expression through microRNA dysregulation in HIV-related non Hodgkin lymphomas. Infect Agent Cancer. 2015; 9:41. PMC: 4334912. DOI: 10.1186/1750-9378-9-41. View

Gillet N, Malani N, Melamed A, Gormley N, Carter R, Bentley D . The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones. Blood. 2011; 117(11):3113-22. PMC: 3062313. DOI: 10.1182/blood-2010-10-312926. View

Schraml B, Hildner K, Ise W, Lee W, Smith W, Solomon B . The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature. 2009; 460(7253):405-9. PMC: 2716014. DOI: 10.1038/nature08114. View

Schermelleh L, Haemmer A, Spada F, Rosing N, Meilinger D, Rothbauer U . Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation. Nucleic Acids Res. 2007; 35(13):4301-12. PMC: 1934996. DOI: 10.1093/nar/gkm432. View

10.

Suzuki M, Kerr A, De Sousa D, Bird A . CpG methylation is targeted to transcription units in an invertebrate genome. Genome Res. 2007; 17(5):625-31. PMC: 1855171. DOI: 10.1101/gr.6163007. View

11.

Doke M, Jeganathan V, McLaughlin J, Samikkannu T . HIV-1 Tat and cocaine impact mitochondrial epigenetics: effects on DNA methylation. Epigenetics. 2020; 16(9):980-999. PMC: 8451453. DOI: 10.1080/15592294.2020.1834919. View

12.

Greenwood E, Williamson J, Sienkiewicz A, Naamati A, Matheson N, Lehner P . Promiscuous Targeting of Cellular Proteins by Vpr Drives Systems-Level Proteomic Remodeling in HIV-1 Infection. Cell Rep. 2019; 27(5):1579-1596.e7. PMC: 6506760. DOI: 10.1016/j.celrep.2019.04.025. View

13.

Pham D, Moseley C, Gao M, Savic D, Winstead C, Sun M . Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf. Cell Rep. 2019; 29(5):1203-1220.e7. PMC: 7182170. DOI: 10.1016/j.celrep.2019.09.064. View

14.

Shalginskikh N, Poleshko A, Skalka A, Katz R . Retroviral DNA methylation and epigenetic repression are mediated by the antiviral host protein Daxx. J Virol. 2012; 87(4):2137-50. PMC: 3571491. DOI: 10.1128/JVI.02026-12. View

15.

Busslinger M, Tarakhovsky A . Epigenetic control of immunity. Cold Spring Harb Perspect Biol. 2014; 6(6). PMC: 4031963. DOI: 10.1101/cshperspect.a019307. View

16.

MacDonald J, Gin C, Roskams A . Stage-specific induction of DNA methyltransferases in olfactory receptor neuron development. Dev Biol. 2005; 288(2):461-73. DOI: 10.1016/j.ydbio.2005.09.048. View

17.

Arzate-Mejia R, Recillas-Targa F, Corces V . Developing in 3D: the role of CTCF in cell differentiation. Development. 2018; 145(6). PMC: 5897592. DOI: 10.1242/dev.137729. View

18.

Robertson K . DNA methylation and human disease. Nat Rev Genet. 2005; 6(8):597-610. DOI: 10.1038/nrg1655. View

19.

Xi Y, Li W . BSMAP: whole genome bisulfite sequence MAPping program. BMC Bioinformatics. 2009; 10:232. PMC: 2724425. DOI: 10.1186/1471-2105-10-232. View

20.

Laguette N, Bregnard C, Hue P, Basbous J, Yatim A, Larroque M . Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell. 2014; 156(1-2):134-45. DOI: 10.1016/j.cell.2013.12.011. View