Gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with SIV or SHIV

Vickie A. Marshall, Nazzarena Labo, Xing Pei Hao, Benjamin Holdridge, Marshall Thompson, Wendell Miley, Catherine Brands, Vicky Coalter, Rebecca Kiser, Miriam Anver, Yelena Golubeva, Andrew Warner, Elaine S. Jaffe, Michael Piatak, Scott W. Wong, Claes Ohlen, Rhonda MacAllister, Jeremy Smedley, Claire Deleage, Gregory Q. Del PreteJeffrey D. Lifson, Jacob D. Estes, Denise Whitby

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Human gammaherpesviruses are associated with malignancies in HIV infected individuals; in macaques used in non-human primate models of HIV infection, gammaherpesvirus infections also occur. Limited data on prevalence and tumorigenicity of macaque gammaherpesviruses, mostly cross-sectional analyses of small series, are available. We comprehensively examine all three-rhesus macaque gammaherpesviruses -Rhesus rhadinovirus (RRV), Rhesus Lymphocryptovirus (RLCV) and Retroperitoneal Fibromatosis Herpesvirus (RFHV) in macaques experimentally infected with Simian Immunodeficiency Virus or Simian Human Immunodeficiency Virus (SIV/SHIV) in studies spanning 15 years at the AIDS and Cancer Virus Program of the Frederick National Laboratory for Cancer Research. We evaluated 18 animals with malignancies (16 lymphomas, one fibrosarcoma and one carcinoma) and 32 controls. We developed real time quantitative PCR assays for each gammaherpesvirus DNA viral load (VL) in malignant and non-tumor tissues; we also characterized the tumors using immunohistochemistry and in situ hybridization. Furthermore, we retrospectively quantified gammaherpesvirus DNA VL and SIV/SHIV RNA VL in longitudinally-collected PBMCs and plasma, respectively. One or more gammaherpesviruses were detected in 17 tumors; generally, one was predominant, and the relevant DNA VL in the tumor was very high compared to surrounding tissues. RLCV was predominant in tumors resembling diffuse large B cell lymphomas; in a Burkitt-like lymphoma, RRV was predominant; and in the fibrosarcoma, RFHV was predominant. Median RRV and RLCV PBMC DNA VL were significantly higher in cases than controls; SIV/SHIV VL and RLCV VL were independently associated with cancer. Local regressions showed that longitudinal VL patterns in cases and controls, from SIV infection to necropsy, differed for each gammaherpesvirus: while RFHV VL increased only slightly in all animals, RLCV and RRV VL increased significantly and continued to increase steeply in cases; in controls, VL flattened. In conclusion, the data suggest that gammaherpesviruses may play a significant role in tumorogenesis in macaques infected with immunodeficiency viruses.

Original languageEnglish (US)
Article numbere1007130
JournalPLoS pathogens
Volume14
Issue number7
DOIs
StatePublished - Jul 2018

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Marshall, V. A., Labo, N., Hao, X. P., Holdridge, B., Thompson, M., Miley, W., Brands, C., Coalter, V., Kiser, R., Anver, M., Golubeva, Y., Warner, A., Jaffe, E. S., Piatak, M., Wong, S. W., Ohlen, C., MacAllister, R., Smedley, J., Deleage, C., ... Whitby, D. (2018). Gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with SIV or SHIV. PLoS pathogens, 14(7), [e1007130]. https://doi.org/10.1371/journal.ppat.1007130