1887

Abstract

Human pegivirus (HPgV; previously called GB virus C/hepatitis G virus) has limited pathogenicity, despite causing persistent infection, and is associated with prolonged survival in human immunodeficiency virus-infected individuals. Although HPgV RNA is found in and produced by T- and B-lymphocytes, the primary permissive cell type(s) are unknown. We quantified HPgV RNA in highly purified CD4 and CD8 T-cells, including naïve, central memory and effector memory populations, and in B-cells (CD19), NK cells (CD56) and monocytes (CD14) using real-time reverse transcription-PCR. Single-genome sequencing was performed on viruses within individual cell types to estimate genetic diversity among cell populations. HPgV RNA was present in CD4 and CD8 T-lymphocytes (nine of nine subjects), B-lymphocytes (seven of ten subjects), NK cells and monocytes (both four of five). HPgV RNA levels were higher in naïve (CD45RA) CD4 cells than in central memory and effector memory cells (<0.01). HPgV sequences were highly conserved among subjects (0.117±0.02 substitutions per site; range 0.58–0.14) and within subjects (0.006±0.003 substitutions per site; range 0.006–0.010). The non-synonymous/synonymous substitution ratio was 0.07, suggesting a low selective pressure. Carboxyfluorescein succinimidyl ester (CFSE)-labelled HPgV RNA-containing particles precipitated by a commercial exosome isolation reagent delivered CSFE to uninfected monocytes, NK cells and T- and B-lymphocytes, and HPgV RNA was transferred to PBMCs with evidence of subsequent virus replication. Thus, HPgV RNA-containing serum particles including microvesicles may contribute to delivery of HPgV to PBMCs , explaining the apparent broad tropism of this persistent human RNA virus.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.063016-0
2014-06-01
2019-11-13
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/6/1307.html?itemId=/content/journal/jgv/10.1099/vir.0.063016-0&mimeType=html&fmt=ahah

References

  1. Adams M. J. , King A. M. Q. , Carstens E. B. . ( 2013; ). Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2013). . Arch Virol 158:, 2023–2030. [CrossRef] [PubMed]
    [Google Scholar]
  2. Agnello V. , Abel G. , Elfahal M. , Knight G. B. , Zhang Q. X. . ( 1999; ). Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor. . Proc Natl Acad Sci U S A 96:, 12766–12771. [CrossRef] [PubMed]
    [Google Scholar]
  3. Alberts B. , Johnson A. , Lewis J. , Raff M. , Roberts K. , Walter P. . ( 2002; ). Molecular Biology of the Cell, , 4th edn.. New York:: Garland Science;.
    [Google Scholar]
  4. Berg T. , Müller A. R. , Platz K. P. , Höhne M. , Bechstein W.-O. , Hopf U. , Wiedenmann B. , Neuhaus P. , Schreier E. . ( 1999; ). Dynamics of GB virus C viremia early after orthotopic liver transplantation indicates extrahepatic tissues as the predominant site of GB virus C replication. . Hepatology 29:, 245–249. [CrossRef] [PubMed]
    [Google Scholar]
  5. Bhattarai N. , Stapleton J. T. . ( 2012; ). GB virus C: the good boy virus?. Trends Microbiol 20:, 124–130. [CrossRef] [PubMed]
    [Google Scholar]
  6. Bhattarai N. , Rydze R. T. , Chivero E. T. , Stapleton J. T. . ( 2012a; ). GB virus C viremia is associated with higher levels of double-negative T cells and lower T-cell activation in HIV-infected individuals receiving antiretroviral therapy. . J Infect Dis 206:, 1469–1472. [CrossRef] [PubMed]
    [Google Scholar]
  7. Bhattarai N. , McLinden J. H. , Xiang J. , Kaufman T. M. , Stapleton J. T. . ( 2012b; ). GB virus C envelope protein E2 inhibits TCR-induced IL-2 production and alters IL-2-signaling pathways. . J Immunol 189:, 2211–2216. [CrossRef] [PubMed]
    [Google Scholar]
  8. Bhattarai N. , McLinden J. H. , Xiang J. , Landay A. L. , Chivero E. T. , Stapleton J. T. . ( 2013; ). GB virus C particles inhibit T cell activation via envelope E2 protein-mediated inhibition of TCR signaling. . J Immunol 190:, 6351–6359. [CrossRef] [PubMed]
    [Google Scholar]
  9. Fan X. , Xu Y. , Solomon H. , Ramrakhiani S. , Neuschwander-Tetri B. A. , Di Bisceglie A. M. . ( 1999; ). Is hepatitis G/GB virus-C virus hepatotropic? Detection of hepatitis G/GB virus-C viral RNA in liver and serum. . J Med Virol 58:, 160–164. [CrossRef] [PubMed]
    [Google Scholar]
  10. Fogeda M. , Navas S. , Martín J. , Casqueiro M. , Rodríguez E. , Arocena C. , Carreño V. . ( 1999; ). In vitro infection of human peripheral blood mononuclear cells by GB virus C/hepatitis G virus. . J Virol 73:, 4052–4061.[PubMed]
    [Google Scholar]
  11. Fogeda M. , López-Alcorocho J. M. , Bartolomé J. , Arocena C. , Martín M. A. , Carreño V. . ( 2000; ). Existence of distinct GB virus C/hepatitis G virus variants with different tropism. . J Virol 74:, 7936–7942. [CrossRef] [PubMed]
    [Google Scholar]
  12. George S. L. , Xiang J. , Stapleton J. T. . ( 2003; ). Clinical isolates of GB virus type C vary in their ability to persist and replicate in peripheral blood mononuclear cell cultures. . Virology 316:, 191–201. [CrossRef] [PubMed]
    [Google Scholar]
  13. George S. L. , Varmaz D. , Stapleton J. T. . ( 2006; ). GB virus C replicates in primary T and B lymphocytes. . J Infect Dis 193:, 451–454. [CrossRef] [PubMed]
    [Google Scholar]
  14. George S. L. , Varmaz D. , Tavis J. E. , Chowdhury A. . ( 2012; ). The GB virus C (GBV-C) NS3 serine protease inhibits HIV-1 replication in a CD4+ T lymphocyte cell line without decreasing HIV receptor expression. . PLoS ONE 7:, e30653. [CrossRef] [PubMed]
    [Google Scholar]
  15. Haase A. T. . ( 1999; ). Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. . Annu Rev Immunol 17:, 625–656. [CrossRef] [PubMed]
    [Google Scholar]
  16. Heringlake S. , Ockenga J. , Tillmann H. L. , Trautwein C. , Meissner D. , Stoll M. , Hunt J. , Jou C. , Solomon N. . & other authors ( 1998; ). GB virus C/hepatitis G virus infection: a favorable prognostic factor in human immunodeficiency virus-infected patients?. J Infect Dis 177:, 1723–1726. [CrossRef] [PubMed]
    [Google Scholar]
  17. Jung S. , Eichenmüller M. , Donhauser N. , Neipel F. , Engel A. M. , Hess G. , Fleckenstein B. , Reil H. . ( 2007; ). HIV entry inhibition by the envelope 2 glycoprotein of GB virus C. . AIDS 21:, 645–647. [CrossRef] [PubMed]
    [Google Scholar]
  18. Kisiel E. , Cortez K. C. , Pawełczyk A. , Ośko I. B. , Kubisa N. , Laskus T. , Radkowski M. . ( 2013; ). Hepatitis G virus/GBV-C in serum, peripheral blood mononuclear cells and bone marrow in patients with hematological malignancies. . Infect Genet Evol 19:, 195–199. [CrossRef] [PubMed]
    [Google Scholar]
  19. Korber B. . ( 2000; ). HIV sequence signatures and similarities. . In Computational and Evolutionary Analysis of HIV Molecular Sequences, pp. 55–72. Edited by Rodgrigo A. G. , Learn G. H. . . Dordrecht, The Netherlands:: Kluwer Academic Publishers;.
    [Google Scholar]
  20. Laskus T. , Radkowski M. , Wang L. F. , Vargas H. , Rakela J. . ( 1997; ). Lack of evidence for hepatitis G virus replication in the livers of patients coinfected with hepatitis C and G viruses. . J Virol 71:, 7804–7806.[PubMed]
    [Google Scholar]
  21. Madejón A. , Fogeda M. , Bartolomé J. , Pardo M. , González C. , Cotonat T. , Carreńo V. . ( 1997; ). GB virus C RNA in serum, liver, and peripheral blood mononuclear cells from patients with chronic hepatitis B, C, and D. . Gastroenterology 113:, 573–578. [CrossRef] [PubMed]
    [Google Scholar]
  22. Maidana-Giret M. T. , Silva T. M. , Sauer M. M. , Tomiyama H. , Levi J. E. , Bassichetto K. C. , Nishiya A. , Diaz R. S. , Sabino E. C. . & other authors ( 2009; ). GB virus type C infection modulates T-cell activation independently of HIV-1 viral load. . AIDS 23:, 2277–2287. [CrossRef] [PubMed]
    [Google Scholar]
  23. Meckes D. G. Jr , Raab-Traub N. . ( 2011; ). Microvesicles and viral infection. . J Virol 85:, 12844–12854. [CrossRef] [PubMed]
    [Google Scholar]
  24. Mellor J. , Haydon G. , Blair C. , Livingstone W. , Simmonds P. . ( 1998; ). Low level or absent in vivo replication of hepatitis C virus and hepatitis G virus/GB virus C in peripheral blood mononuclear cells. . J Gen Virol 79:, 705–714.[PubMed]
    [Google Scholar]
  25. Mohr E. L. , Stapleton J. T. . ( 2009; ). GB virus type C interactions with HIV: the role of envelope glycoproteins. . J Viral Hepat 16:, 757–768. [CrossRef] [PubMed]
    [Google Scholar]
  26. Nunnari G. , Nigro L. , Palermo F. , Attanasio M. , Berger A. , Doerr H. W. , Pomerantz R. J. , Cacopardo B. . ( 2003; ). Slower progression of HIV-1 infection in persons with GB virus C co-infection correlates with an intact T-helper 1 cytokine profile. . Ann Intern Med 139:, 26–30. [CrossRef] [PubMed]
    [Google Scholar]
  27. Pessoa M. G. , Terrault N. A. , Detmer J. , Kolberg J. , Collins M. , Hassoba H. M. , Wright T. L. . ( 1998; ). Quantitation of hepatitis G and C viruses in the liver: evidence that hepatitis G virus is not hepatotropic. . Hepatology 27:, 877–880. [CrossRef] [PubMed]
    [Google Scholar]
  28. Radkowski M. , Kubicka J. , Kisiel E. , Cianciara J. , Nowicki M. , Rakela J. , Laskus T. . ( 2000; ). Detection of active hepatitis C virus and hepatitis G virus/GB virus C replication in bone marrow in human subjects. . Blood 95:, 3986–3989.[PubMed]
    [Google Scholar]
  29. Rey D. , Vidinic-Moularde J. , Meyer P. , Schmitt C. , Fritsch S. , Lang J. M. , Stoll-Keller F. . ( 2000; ). High prevalence of GB virus C/hepatitis G virus RNA and antibodies in patients infected with human immunodeficiency virus type 1. . Eur J Clin Microbiol Infect Dis 19:, 721–724. [CrossRef] [PubMed]
    [Google Scholar]
  30. Rydze R. T. , Bhattarai N. , Stapleton J. T. . ( 2012; ). GB virus C infection is associated with a reduced rate of reactivation of latent HIV and protection against activation-induced T-cell death. . Antivir Ther 17:, 1271–1279. [CrossRef] [PubMed]
    [Google Scholar]
  31. Saito S. , Tanaka K. , Kondo M. , Morita K. , Kitamura T. , Kiba T. , Numata K. , Sekihara H. . ( 1997; ). Plus- and minus-stranded hepatitis G virus RNA in liver tissue and in peripheral blood mononuclear cells. . Biochem Biophys Res Commun 237:, 288–291. [CrossRef] [PubMed]
    [Google Scholar]
  32. Shimizu Y. K. , Hijikata M. , Kiyohara T. , Kitamura Y. , Yoshikura H. . ( 1999; ). Replication of GB virus C (hepatitis G virus) in interferon-resistant Daudi cells. . J Virol 73:, 8411–8414.[PubMed]
    [Google Scholar]
  33. Smith D. B. , Bukh J. , Kuiken C. , Muerhoff A. S. , Rice C. M. , Stapleton J. T. , Simmonds P. . ( 2014; ). Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment Web resource. . Hepatology 59:, 318–327. [CrossRef] [PubMed]
    [Google Scholar]
  34. Souza I. E. , Allen J. B. , Xiang J. , Klinzman D. , Diaz R. , Zhang S. , Chaloner K. , Zdunek D. , Hess G. . & other authors ( 2006; ). Effect of primer selection on estimates of GB virus C (GBV-C) prevalence and response to antiretroviral therapy for optimal testing for GBV-C viremia . J Clin Microbiol 44:, 3105–3113. [CrossRef] [PubMed]
    [Google Scholar]
  35. Stapleton J. T. , Chaloner K. , Zhang J. , Klinzman D. , Souza I. E. , Xiang J. , Landay A. , Fahey J. , Pollard R. , Mitsuyasu R. . ( 2009; ). GBV-C viremia is associated with reduced CD4 expansion in HIV-infected people receiving HAART and interleukin-2 therapy. . AIDS 23:, 605–610. [CrossRef] [PubMed]
    [Google Scholar]
  36. Stapleton J. T. , Foung S. , Muerhoff A. S. , Bukh J. , Simmonds P. . ( 2011; ). The GB viruses: a review and proposed classification of GBV-A, GBV-C (HGV), and GBV-D in genus Pegivirus within the family Flaviviridae . . J Gen Virol 92:, 233–246. [CrossRef] [PubMed]
    [Google Scholar]
  37. Stapleton J. T. , Bukh J. , Muerhoff A. S. , Foung S. , Simmonds P. . ( 2012a; ). Assignment of human, simian and bat pegiviruses (previously described as GBV-A, GBV-C, and GBV-D) as members of a new Genus (Pegivirus) within the Flaviviridae. ICTV Official Taxonomy: Updates since the 8th Report. . http://talk.ictvonline.org/files/ictv_official_taxonomy_updates_since_the_8th_report/m/vertebrate-official/4486.aspx.
  38. Stapleton J. T. , Chaloner K. , Martenson J. A. , Zhang J. , Klinzman D. , Xiang J. , Sauter W. , Desai S. N. , Landay A. . ( 2012b; ). GB virus C infection is associated with altered lymphocyte subset distribution and reduced T cell activation and proliferation in HIV-infected individuals. . PLoS ONE 7:, e50563. [CrossRef] [PubMed]
    [Google Scholar]
  39. Stapleton J. T. , Martinson J. A. , Klinzman D. , Xiang J. , Desai S. N. , Landay A. . ( 2013; ). GB virus C infection and B-cell, natural killer cell, and monocyte activation markers in HIV-infected individuals. . AIDS 27:, 1829–1832. [CrossRef] [PubMed]
    [Google Scholar]
  40. Tamura K. , Peterson D. , Peterson N. , Stecher G. , Nei M. , Kumar S. . ( 2011; ). mega5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. . Mol Biol Evol 28:, 2731–2739. [CrossRef] [PubMed]
    [Google Scholar]
  41. Tillmann H. L. , Heiken H. , Knapik-Botor A. , Heringlake S. , Ockenga J. , Wilber J. C. , Goergen B. , Detmer J. , McMorrow M. . & other authors ( 2001; ). Infection with GB virus C and reduced mortality among HIV-infected patients. . N Engl J Med 345:, 715–724. [CrossRef] [PubMed]
    [Google Scholar]
  42. Toyoda H. , Fukuda Y. , Hayakawa T. , Takamatsu J. , Saito H. . ( 1998; ). Effect of GB virus C/hepatitis G virus coinfection on the course of HIV infection in hemophilia patients in Japan. . J Acquir Immune Defic Syndr Hum Retrovirol 17:, 209–213. [CrossRef] [PubMed]
    [Google Scholar]
  43. Tucker T. J. , Smuts H. E. M. , Eedes C. , Knobel G. D. , Eickhaus P. , Robson S. C. , Kirsch R. E. . ( 2000; ). Evidence that the GBV-C/hepatitis G virus is primarily a lymphotropic virus. . J Med Virol 61:, 52–58. [CrossRef] [PubMed]
    [Google Scholar]
  44. Vahidnia F. , Petersen M. , Stapleton J. T. , Rutherford G. W. , Busch M. , Custer B. . ( 2012; ). Acquisition of GB virus type C and lower mortality in patients with advanced HIV disease. . Clin Infect Dis 55:, 1012–1019. [CrossRef] [PubMed]
    [Google Scholar]
  45. Williams C. F. , Klinzman D. , Yamashita T. E. , Xiang J. , Polgreen P. M. , Rinaldo C. , Liu C. , Phair J. , Margolick J. B. . & other authors ( 2004; ). Persistent GB virus C infection and survival in HIV-infected men. . N Engl J Med 350:, 981–990. [CrossRef] [PubMed]
    [Google Scholar]
  46. Xiang J. , Klinzman D. , McLinden J. , Schmidt W. N. , LaBrecque D. R. , Gish R. , Stapleton J. T. . ( 1998; ). Characterization of hepatitis G virus (GB-C virus) particles: evidence for a nucleocapsid and expression of sequences upstream of the E1 protein. . J Virol 72:, 2738–2744.[PubMed]
    [Google Scholar]
  47. Xiang J. , Wünschmann S. , Schmidt W. , Shao J. , Stapleton J. T. . ( 2000; ). Full-length GB virus C (Hepatitis G virus) RNA transcripts are infectious in primary CD4-positive T cells. . J Virol 74:, 9125–9133. [CrossRef] [PubMed]
    [Google Scholar]
  48. Xiang J. , Wünschmann S. , Diekema D. J. , Klinzman D. , Patrick K. D. , George S. L. , Stapleton J. T. . ( 2001; ). Effect of coinfection with GB virus C on survival among patients with HIV infection. . N Engl J Med 345:, 707–714. [CrossRef] [PubMed]
    [Google Scholar]
  49. Xiang J. , George S. L. , Wunschmann S. , Chang Q. , Klinzman D. , Stapleton J. T. . ( 2004; ). GB virus C infection inhibits HIV-1 replication by increasing RANTES, MIP-1α, MIP-1β, and SDF-1. . Lancet 363:, 2040–2046.[PubMed] [CrossRef]
    [Google Scholar]
  50. Xiang J. , McLinden J. H. , Chang Q. , Kaufman T. M. , Stapleton J. T. . ( 2006; ). An 85-aa segment of the GB virus type C NS5A phosphoprotein inhibits HIV-1 replication in CD4+ Jurkat T cells. . Proc Natl Acad Sci U S A 103:, 15570–15575. [CrossRef] [PubMed]
    [Google Scholar]
  51. Xiang J. , McLinden J. H. , Kaufman T. M. , Mohr E. L. , Bhattarai N. , Chang Q. , Stapleton J. T. . ( 2012; ). Characterization of a peptide domain within the GB virus C envelope glycoprotein (E2) that inhibits HIV replication. . Virology 430:, 53–62. [CrossRef] [PubMed]
    [Google Scholar]
  52. Zhang W. , Chaloner K. , Tillmann H. L. , Williams C. F. , Stapleton J. T. . ( 2006; ). Effect of early and late GB virus C viraemia on survival of HIV-infected individuals: a meta-analysis. . HIV Med 7:, 173–180. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.063016-0
Loading
/content/journal/jgv/10.1099/vir.0.063016-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error