Reactivation of Chromosomally Integrated Human Herpesvirus-6 by Telomeric Circle Formation


More than 95% of the human population is infected with human herpesvirus-6 (HHV-6) during early childhood and maintains latent HHV-6 genomes either in an extra-chromosomal form or as a chromosomally integrated HHV-6 (ciHHV-6). In addition, approximately 1% of humans are born with an inheritable form of ciHHV-6 integrated into the telomeres of chromosomes. Immunosuppression and stress conditions can reactivate latent HHV-6 replication, which is associated with clinical complications and even death. We have previously shown that Chlamydia trachomatis infection reactivates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. Here, we propose a model and provide experimental evidence for the mechanism of ciHHV-6 reactivation. Infection with Chlamydia induced a transient shortening of telomeric ends, which subsequently led to increased telomeric circle (t-circle) formation and incomplete reconstitution of circular viral genomes containing single viral direct repeat (DR). Correspondingly, short t-circles containing parts of the HHV-6 DR were detected in cells from individuals with genetically inherited ciHHV-6. Furthermore, telomere shortening induced in the absence of Chlamydia infection also caused circularization of ciHHV-6, supporting a t-circle based mechanism for ciHHV-6 reactivation.


Vyšlo v časopise: Reactivation of Chromosomally Integrated Human Herpesvirus-6 by Telomeric Circle Formation. PLoS Genet 9(12): e32767. doi:10.1371/journal.pgen.1004033
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004033

Souhrn

More than 95% of the human population is infected with human herpesvirus-6 (HHV-6) during early childhood and maintains latent HHV-6 genomes either in an extra-chromosomal form or as a chromosomally integrated HHV-6 (ciHHV-6). In addition, approximately 1% of humans are born with an inheritable form of ciHHV-6 integrated into the telomeres of chromosomes. Immunosuppression and stress conditions can reactivate latent HHV-6 replication, which is associated with clinical complications and even death. We have previously shown that Chlamydia trachomatis infection reactivates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. Here, we propose a model and provide experimental evidence for the mechanism of ciHHV-6 reactivation. Infection with Chlamydia induced a transient shortening of telomeric ends, which subsequently led to increased telomeric circle (t-circle) formation and incomplete reconstitution of circular viral genomes containing single viral direct repeat (DR). Correspondingly, short t-circles containing parts of the HHV-6 DR were detected in cells from individuals with genetically inherited ciHHV-6. Furthermore, telomere shortening induced in the absence of Chlamydia infection also caused circularization of ciHHV-6, supporting a t-circle based mechanism for ciHHV-6 reactivation.


Zdroje

1. Tanaka-TayaK, SashiharaJ, KurahashiH, AmoK, MiyagawaH, et al. (2004) Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA. J Med Virol 73: 465–473.

2. ArbuckleJH, MedveczkyMM, LukaJ, HadleySH, LuegmayrA, et al. (2010) The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proc Natl Acad Sci USA 107: 5563–5568.

3. DaibataM, TaguchiT, NemotoY, TaguchiH, MiyoshiI (1999) Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood 94: 1545.

4. ClarkDA (2000) Human herpesvirus 6. Rev Med Virol 10: 155–173.

5. Campadelli-FiumeG, MirandolaP, MenottiL (1999) Human herpesvirus 6: An emerging pathogen. Emerg Infect Dis 5: 353–366.

6. PellettPE, AblashiDV, AmbrosPF, AgutH, CasertaMT, et al. (2012) Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol 22: 144–155.

7. SeeleyWW, MartyFM, HolmesTM, UpchurchK, SoifferRJ, et al. (2007) Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurol 69: 156–165.

8. AblashiDV, EastmanHB, OwenCB, RomanMM, FriedmanJ, et al. (2000) Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol 16: 179–191.

9. BertiR, BrennanMB, SoldanSS, OhayonJM, CasaretoL, et al. (2002) Increased detection of serum HHV-6 DNA sequences during multiple sclerosis (MS) exacerbations and correlation with parameters of MS disease progression. J Neurovirol 8: 250–256.

10. ChapenkoS, MillersA, NoraZ, LoginaI, KukaineR, et al. (2003) Correlation between HHV-6 reactivation and multiple sclerosis disease activity. J Med Virol 69: 111–117.

11. LindquesterGJ, PellettPE (1991) Properties of the human herpesvirus 6 strain Z29 genome: G+C content, length, and presence of variable-length directly repeated terminal sequence elements. Virol 182: 102–110.

12. AchourA, MaletI, DebackC, BonnafousP, BoutolleauD, et al. (2009) Length variability of telomeric repeat sequences of human herpesvirus 6 DNA. J Virol Methods 159: 127–130.

13. GompelsUA, MacaulayHA (1995) Characterization of human telomeric repeat sequences from human herpesvirus 6 and relationship to replication. J Gen Virol 76 (Pt 2) 451–458.

14. MorissetteG, FlamandL (2010) Herpesviruses and chromosomal integration. J Virol 84: 12100–12109.

15. KauferBB, JarosinskiKW, OsterriederN (2011) Herpesvirus telomeric repeats facilitate genomic integration into host telomeres and mobilization of viral DNA during reactivation. J Exp Med 208: 605–615.

16. HuangY, Hidalgo-BravoA, ZhangE, CottonVE, Mendez-BermudezA, et al. (2013) Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. Nucleic Acids Research [Epub ahead of print].

17. PrustyBK, SieglC, HauckP, HainJ, KorhonenSJ, et al. (2013) Chlamydia trachomatis Infection Induces Replication of Latent HHV-6. PLoS ONE 8: e61400.

18. de LangeT (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19: 2100–2110.

19. CesareAJ, ReddelRR (2008) Telomere uncapping and alternative lengthening of telomeres. Mech Ageing Dev 129: 99–108.

20. TomaskaL, NosekJ, KramaraJ, GriffithJD (2009) Telomeric circles: universal players in telomere maintenance? Nat Struct Mol Biol 16: 1010–1015.

21. BraultME, AutexierC (2011) Telomeric recombination induced by dysfunctional telomeres. Mol Biol Cell 22: 179–188.

22. Eckert-BouletN, LisbyM (2010) Regulation of homologous recombination at telomeres in budding yeast. FEBS letters 584: 3696–3702.

23. BrewerBJ, FangmanWL (1987) The localization of replication origins on ARS plasmids in S. cerevisiae. Cell 51: 463–471.

24. CohenS, MechaliM (2002) Formation of extrachromosomal circles from telomeric DNA in Xenopus laevis. EMBO reports 3: 1168–1174.

25. WangRC, SmogorzewskaA, de LangeT (2004) Homologous recombination generates T-loop-sized deletions at human telomeres. Cell 119: 355–368.

26. PickettHA, CesareAJ, JohnstonRL, NeumannAA, ReddelRR (2009) Control of telomere length by a trimming mechanism that involves generation of t-circles. EMBO J 28: 799–809.

27. CesareAJ, GriffithJD (2004) Telomeric DNA in ALT cells is characterized by free telomeric circles and heterogeneous t-loops. Mol Cell Biol 24: 9948–9957.

28. CesareAJ, Groff-VindmanC, ComptonSA, McEachernMJ, GriffithJD (2008) Telomere loops and homologous recombination-dependent telomeric circles in a Kluyveromyces lactis telomere mutant strain. Mol Cell Biol 28: 20–29.

29. CaretteJE, GuimaraesCP, VaradarajanM, ParkAS, WuethrichI, et al. (2009) Haploid genetic screens in human cells identify host factors used by pathogens. Science 326: 1231–1235.

30. de LangeT (2002) Protection of mammalian telomeres. Oncogene 21: 532–540.

31. ChapenkoS, KruminaA, KozirevaS, NoraZ, SultanovaA, et al. (2006) Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome. J Clin Virol 37 Suppl 1: S47–51.

32. PrustyBK, BohmeL, BergmannB, SieglC, KrauseE, et al. (2012) Imbalanced oxidative stress causes chlamydial persistence during non-productive human herpes virus co-infection. PloS one 7: e47427.

33. StameyFR, DominguezG, BlackJB, DambaughTR, PellettPE (1995) Intragenomic linear amplification of human herpesvirus 6B oriLyt suggests acquisition of oriLyt by transposition. J Virol 69: 589–596.

34. MartinME, ThomsonBJ, HonessRW, CraxtonMA, GompelsUA, et al. (1991) The genome of human herpesvirus 6: maps of unit-length and concatemeric genomes for nine restriction endonucleases. J Gen Virol 72 (Pt 1) 157–168.

35. ThomsonBJ, DewhurstS, GrayD (1994) Structure and heterogeneity of the a sequences of human herpesvirus 6 strain variants U1102 and Z29 and identification of human telomeric repeat sequences at the genomic termini. J Virol 68: 3007–3014.

36. DominguezG, DambaughTR, StameyFR, DewhurstS, InoueN, et al. (1999) Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol 73: 8040–8052.

37. BorensteinR, FrenkelN (2009) Cloning human herpes virus 6A genome into bacterial artificial chromosomes and study of DNA replication intermediates. Proc Natl Acad Sci USA 106: 19138–19143.

38. OganesianL, KarlsederJ (2011) Mammalian 5′ C-rich telomeric overhangs are a mark of recombination-dependent telomere maintenance. Molecular Cell 42: 224–236.

39. BorensteinR, ZeigermanH, FrenkelN (2010) The DR1 and DR6 first exons of human herpesvirus 6A are not required for virus replication in culture and are deleted in virus stocks that replicate well in T-cell lines. J Virol 84: 2648–2656.

40. ArbuckleJH, PantrySN, MedveczkyMM, PrichettJ, LoomisKS, et al. (2013) Mapping the telomere integrated genome of human herpesvirus 6A and 6B. Virol 442: 3–11.

41. WilliamsES, BaileySM (2009) Chromosome orientation fluorescence in situ hybridization (CO-FISH). Cold Spring Harb Protoc 2009 pdb prot5269.

42. RechnerC, KühleweinC, MüllerA, SchildH, RudelT (2007) Host glycoprotein Gp96 and scavenger receptor SREC interact with PorB of disseminating Neisseria gonorrhoeae in an epithelial invasion pathway. Cell Host Microbe 2: 393–403.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2013 Číslo 12
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa