Unintegrated HIV-1 DNAs Are Loaded with Core and Linker Histones and Transcriptionally Silenced

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 Nov 6

PMID 31685613

Citations 36

Authors

Franziska K Geis

Stephen P Goff

Affiliations

Soon will be listed here.

Abstract

Upon delivery into the nucleus of the host cell, linear double-stranded retroviral DNAs are either integrated into the host genome to form the provirus or act as a target of the DNA damage response and become circularized. Little is known about the chromatinization status of the unintegrated retroviral DNAs of the human immunodeficiency virus type 1 (HIV-1). In this study, we used chromatin immunoprecipitation to investigate the nature of unintegrated HIV-1 DNAs and discovered that core histones, the histone variant H3.3, and H1 linker histones are all deposited onto extrachromosomal HIV-1 DNA. We performed a time-course analysis and determined that the loading of core and linker histones occurred early after virus application. H3.3 and H1 linker histones were also found to be loaded onto unintegrated DNAs of the Moloney murine leukemia virus. The unintegrated retroviral DNAs are potently silenced, and we provide evidence that the suppression of extrachromosomal HIV-1 DNA is histone-related. Unintegrated DNAs were marked by posttranslational histone modifications characteristic of transcriptionally inactive genes: high levels of H3K9 trimethylation and low levels of H3 acetylation. These findings reveal insights into the nature of unintegrated retroviral DNAs.

Citing Articles

The role of genetic diversity, epigenetic regulation, and sex-based differences in HIV cure research: a comprehensive review.

Letchumanan P, Das K Epigenetics Chromatin. 2025; 18(1):1.

PMID: 39754177 PMC: 11697457. DOI: 10.1186/s13072-024-00564-4.

CRL4-DCAF1 Ubiquitin Ligase Dependent Functions of HIV Viral Protein R and Viral Protein X.

Dobransky A, Root M, Hafner N, Marcum M, Sharifi H Viruses. 2024; 16(8).

PMID: 39205287 PMC: 11360348. DOI: 10.3390/v16081313.

Chromatin Immunoprecipitation of Retroviral Genomes with Antibodies Recognizing Modified Histones and Specific Viral Proteins.

Geis F, Goff S Methods Mol Biol. 2024; 2807:163-171.

PMID: 38743228 DOI: 10.1007/978-1-0716-3862-0_12.

Brief Histories of Retroviral Integration Research and Associated International Conferences.

Grandgenett D, Engelman A Viruses. 2024; 16(4).

PMID: 38675945 PMC: 11054761. DOI: 10.3390/v16040604.

PTEN Mediates the Silencing of Unintegrated HIV-1 DNA.

Phan A, Zhu Y Viruses. 2024; 16(2).

PMID: 38400066 PMC: 10892664. DOI: 10.3390/v16020291.

References

Lewis P, Emerman M . Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J Virol. 1994; 68(1):510-6. PMC: 236313. DOI: 10.1128/JVI.68.1.510-516.1994. View

Hake S, Garcia B, Kauer M, Baker S, Shabanowitz J, Hunt D . Serine 31 phosphorylation of histone variant H3.3 is specific to regions bordering centromeres in metaphase chromosomes. Proc Natl Acad Sci U S A. 2005; 102(18):6344-9. PMC: 1088391. DOI: 10.1073/pnas.0502413102. View

Elsasser S, Noh K, Diaz N, Allis C, Banaszynski L . Elsässer et al. reply. Nature. 2017; 548(7665):E7-E9. DOI: 10.1038/nature23278. View

Pelascini L, Janssen J, Goncalves M . Histone deacetylase inhibition activates transgene expression from integration-defective lentiviral vectors in dividing and non-dividing cells. Hum Gene Ther. 2012; 24(1):78-96. PMC: 3555116. DOI: 10.1089/hum.2012.069. View

Yan J, Shun M, Zhang Y, Hao C, Skowronski J . HIV-1 Vpr counteracts HLTF-mediated restriction of HIV-1 infection in T cells. Proc Natl Acad Sci U S A. 2019; 116(19):9568-9577. PMC: 6511057. DOI: 10.1073/pnas.1818401116. View

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

Harshman S, Young N, Parthun M, Freitas M . H1 histones: current perspectives and challenges. Nucleic Acids Res. 2013; 41(21):9593-609. PMC: 3834806. DOI: 10.1093/nar/gkt700. View

Goh W, Rogel M, Kinsey C, Michael S, Fultz P, Nowak M . HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo. Nat Med. 1998; 4(1):65-71. DOI: 10.1038/nm0198-065. View

BUKRINSKAYA A, Brichacek B, Mann A, Stevenson M . Establishment of a functional human immunodeficiency virus type 1 (HIV-1) reverse transcription complex involves the cytoskeleton. J Exp Med. 1998; 188(11):2113-25. PMC: 2212381. DOI: 10.1084/jem.188.11.2113. View

10.

Elsasser S, Noh K, Diaz N, Allis C, Banaszynski L . Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature. 2015; 522(7555):240-244. PMC: 4509593. DOI: 10.1038/nature14345. View

11.

Lewis P, Hensel M, Emerman M . Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J. 1992; 11(8):3053-8. PMC: 556788. DOI: 10.1002/j.1460-2075.1992.tb05376.x. View

12.

Hazuda D, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler J . Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science. 2000; 287(5453):646-50. DOI: 10.1126/science.287.5453.646. View

13.

Bush K, Yuen B, Barrilleaux B, Riggs J, OGeen H, Cotterman R . Endogenous mammalian histone H3.3 exhibits chromatin-related functions during development. Epigenetics Chromatin. 2013; 6(1):7. PMC: 3635903. DOI: 10.1186/1756-8935-6-7. View

14.

Rai T, Glass M, Cole J, Rather M, Marsden M, Neilson M . Histone chaperone HIRA deposits histone H3.3 onto foreign viral DNA and contributes to anti-viral intrinsic immunity. Nucleic Acids Res. 2017; 45(20):11673-11683. PMC: 5691367. DOI: 10.1093/nar/gkx771. View

15.

Yamano T, Ura K, Morishita R, Nakajima H, Monden M, Kaneda Y . Amplification of transgene expression in vitro and in vivo using a novel inhibitor of histone deacetylase. Mol Ther. 2000; 1(6):574-80. DOI: 10.1006/mthe.2000.0074. View

16.

Foss S, Watkinson R, Sandlie I, James L, Andersen J . TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. Immunol Rev. 2015; 268(1):328-39. PMC: 4670481. DOI: 10.1111/imr.12363. View

17.

Nan X, Hyndman L, Agbi N, Porteous D, Boyd A . Potent stimulation of gene expression by histone deacetylase inhibitors on transiently transfected DNA. Biochem Biophys Res Commun. 2004; 324(1):348-54. DOI: 10.1016/j.bbrc.2004.09.055. View

18.

Sabo Y, Walsh D, Barry D, Tinaztepe S, de Los Santos K, Goff S . HIV-1 induces the formation of stable microtubules to enhance early infection. Cell Host Microbe. 2013; 14(5):535-46. PMC: 3855456. DOI: 10.1016/j.chom.2013.10.012. View

19.

Yurkovetskiy L, Guney M, Kim K, Goh S, McCauley S, Dauphin A . Primate immunodeficiency virus proteins Vpx and Vpr counteract transcriptional repression of proviruses by the HUSH complex. Nat Microbiol. 2018; 3(12):1354-1361. PMC: 6258279. DOI: 10.1038/s41564-018-0256-x. View

20.

Zhu Y, Wang G, Cingoz O, Goff S . NP220 mediates silencing of unintegrated retroviral DNA. Nature. 2018; 564(7735):278-282. PMC: 6349045. DOI: 10.1038/s41586-018-0750-6. View