Medical Microbiology and Immunology

, Volume 208, Issue 1, pp 109–129 | Cite as

Macaca arctoides gammaherpesvirus 1 (strain herpesvirus Macaca arctoides): virus sequence, phylogeny and characterisation of virus-transformed macaque and rabbit cell lines

  • Andi KrumbholzEmail author
  • Janine Roempke
  • Thomas Liehr
  • Marco Groth
  • Astrid Meerbach
  • Michael Schacke
  • Gregor Maschkowitz
  • Helmut Fickenscher
  • Wolfram Klapper
  • Andreas Sauerbrei
  • Peter Wutzler
  • Roland Zell
Original Investigation


Herpesvirus Macaca arctoides (HVMA) has the propensity to transform macaque lymphocytes to lymphoblastoid cells (MAL-1). Inoculation of rabbits with cell-free virus-containing supernatant resulted in the development of malignant lymphomas and allowed isolation of immortalised HVMA-transformed rabbit lymphocytes (HTRL). In this study, the HVMA genome sequence (approx. 167 kbp), its organisation, and novel aspects of virus latency are presented. Ninety-one open reading frames were identified, of which 86 were non-repetitive. HVMA was identified as a Lymphocryptovirus closely related to Epstein–Barr virus, suggesting the designation as ‘Macaca arctoides gammaherpesvirus 1’ (MarcGHV-1). In situ lysis gel and Southern blot hybridisation experiments revealed that the MAL-1 cell line contains episomal and linear DNA, whereas episomal DNA is predominantly present in HTRL. Integration of viral DNA into macaque and rabbit host cell genomes was demonstrated by fluorescence in situ hybridisation on chromosomal preparations. Analysis of next-generation sequencing data confirmed this finding. Approximately 400 read pairs represent the overlap between macaque and MarcGHV-1 DNA. Both, MAL-1 cells and HTRL show characteristics of a polyclonal tumour with B- and T-lymphocyte markers. Based on analysis of viral gene expression and immunohistochemistry, the persistence of MarcGHV-1 in MAL-1 cells resemble the latency type III, whereas the expression pattern observed in HTRL was more comparable with latency type II. There was no evidence of the presence of STLV-1 proviral DNA in MAL-1 and HTRL. Due to the similarity to EBV-mediated cell transformation, MarcGHV-1 expands the available in vitro models by simian and rabbit cell lines.


Lymphocryptovirus Old World monkey Genome sequence Lymphocytes Tumour 



We thank the Institute of Clinical Molecular Biology (ICMB) in Kiel for providing Sanger sequencing facilities as supported in part by the DFG Cluster of Excellence “Inflammation at Interfaces” and “Future Ocean”. We thank the technicians S. Greve, T. Henke, C. Noack, C. Botz von Drathen, M. Müller, I. Görlich and Dr. N. Kosyakova for excellent technical support. The authors would like to thank Dr. K. Korn (Virological Institute, University of Erlangen-Nuremberg, Erlangen, Germany) for providing a HTLV-1-positive DNA sample with known proviral load. Furthermore, authors are indebted to Dr. L. Harder (Institute of Tumour Genetics, Kiel, Germany) and R. Bunke, M.D. (Wietze, Germany) for critical reading of the manuscript and valuable comments.

Author contributions

AK, RZ, HF, AS, AM, and PW planned the experiments; MS generated HTRL and performed initial characterisation; JR and MG performed sequencing with help of AK and RZ; these data were then analysed by JR, MG, AK, and RZ and used for phylogenetic comparisons; JR performed in situ lysis gel and Southern blot, and produced cloned MarcGHV-1 DNA for synthesis of FISH probes; chromosomal analysis and FISH were done by TL; AK, JR, and MG performed analysis of transcripts as well as STLV-1/HTLV-1 proviral DNA search; ISH and IHC were done by AK, GM and WK; AK, JR, TL and RZ wrote the paper; all authors approved the final version. Parts of this manuscript are subject of the MD thesis of JR.


This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Ethical statement

Nothing to declare.

Conflict of interest

The authors declare no financial conflict of interest and no non-financial conflict of interest.

Supplementary material

430_2018_565_MOESM1_ESM.docx (4 mb)
Supplementary material 1 (DOCX 4116 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Andi Krumbholz
    • 1
    Email author
  • Janine Roempke
    • 1
  • Thomas Liehr
    • 2
  • Marco Groth
    • 3
  • Astrid Meerbach
    • 4
  • Michael Schacke
    • 4
  • Gregor Maschkowitz
    • 1
  • Helmut Fickenscher
    • 1
  • Wolfram Klapper
    • 5
  • Andreas Sauerbrei
    • 4
  • Peter Wutzler
    • 4
  • Roland Zell
    • 4
  1. 1.Institute of Infection MedicineUniversity of Kiel and University Medical Center Schleswig-HolsteinKielGermany
  2. 2.Institute of Human Genetics, Jena University HospitalFriedrich Schiller UniversityJenaGermany
  3. 3.CF DNA sequencingLeibniz Institute on Aging-Fritz Lipmann Institute (FLI)JenaGermany
  4. 4.Division of Experimental Virology, Institute of Medical Microbiology, Jena University HospitalFriedrich Schiller UniversityJenaGermany
  5. 5.Department of Pathology, Hematopathology Section and Lymph Node RegistryUniversity of Kiel and University Medical Center Schleswig-HolsteinKielGermany

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