Structural variation of centromeric endogenous retroviruses in human populations and their impact on cutaneous T-cell lymphoma, Sézary syndrome, and HIV infection

Mark H. Kaplan, Mark Kaminski, Judith M. Estes, Scott D. Gitlin, Joseph Zahn, James T. Elder, Trilokraj Tejasvi, Elizabeth Gensterblum, Amr H. Sawalha, Joseph Patrick McGowan, Michael H. Dosik, Haner Direskeneli, Guher Saruhan Direskeneli, Sally N. Adebamowo, Clement A. Adebamowo, Mohammad Sajadi, Rafael Contreras-Galindo

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background: Human Endogenous Retroviruses type K HML-2 (HK2) are integrated into 117 or more areas of human chromosomal arms while two newly discovered HK2 proviruses, K111 and K222, spread extensively in pericentromeric regions, are the first retroviruses discovered in these areas of our genome. Methods: We use PCR and sequencing analysis to characterize pericentromeric K111 proviruses in DNA from individuals of diverse ethnicities and patients with different diseases. Results: We found that the 5′ LTR-gag region of K111 proviruses is missing in certain individuals, creating pericentromeric instability. K111 deletion (-/- K111) is seen in about 15% of Caucasian, Asian, and Middle Eastern populations; it is missing in 2.36% of African individuals, suggesting that the -/- K111 genotype originated out of Africa. As we identified the -/-K111 genotype in Cutaneous T-cell lymphoma (CTCL) cell lines, we studied whether the -/-K111 genotype is associated with CTCL. We found a significant increase in the frequency of detection of the -/-K111 genotype in Caucasian patients with severe CTCL and/or Sézary syndrome (n = 35, 37.14%), compared to healthy controls (n = 160, 15.6%) [p = 0.011]. The -/-K111 genotype was also found to vary in HIV-1 infection. Although Caucasian healthy individuals have a similar frequency of detection of the -/- K111 genotype, Caucasian HIV Long-Term Non-Progressors (LTNPs) and/or elite controllers, have significantly higher detection of the -/-K111 genotype (30.55%; n = 36) than patients who rapidly progress to AIDS (8.5%; n = 47) [p = 0.0097]. Conclusion: Our data indicate that pericentromeric instability is associated with more severe CTCL and/or Sézary syndrome in Caucasians, and appears to allow T-cells to survive lysis by HIV infection. These findings also provide new understanding of human evolution, as the -/-K111 genotype appears to have arisen out of Africa and is distributed unevenly throughout the world, possibly affecting the severity of HIV in different geographic areas.

Original languageEnglish (US)
Article number58
JournalBMC Medical Genomics
Issue number1
StatePublished - May 2 2019

Bibliographical note

Funding Information:
Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS). MACS Principal Investigators: Johns Hopkins University Bloomberg School of Public Health (Joseph Margolick, Todd Brown), grant U01-AI35042; Northwestern University (Steven Wolinsky), grant U01-AI35039; University of California, Los Angeles (Roger Detels, Otoniel Martinez-Maza, Otto Yang), grant U01-AI35040; University of Pittsburgh (Charles Rinaldo, Lawrence Kingsley, Jeremy Martinson), grant U01-AI35041; the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson, Gypsyamber D’Souza), grant UM1-AI35043. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by grant UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) and the NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS. The MACS website is located at C.A.A. and S.N.A. were supported by the Fogarty International Center of the NIH; grant number D43TW009106; the National Human Genome Research Institute, Grant number U01HG009784; and the National Cancer Institute, grant number 5P30CA134274. This work was supported by a grant 05–5089 from the Concerned Parents for AIDS Research (CPFA) to M.H.K.; grants 1R01AI110259-01A1 and 1I01BX002358-01A1 to M.S.; and a grant K22 CA177824 from the National Cancer Institute to R.C-G. R.C-G is the recipient of a New Investigator Award from the Scleroderma Foundation.

Publisher Copyright:
© 2019 The Author(s).


  • AIDS
  • CTCL
  • Centromeres
  • HERV-K
  • HIV
  • K111
  • Pericentromeric instability

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