Regulation of the human endogenous retrovirus K (HML-2) transcriptome by the HIV-1 Tat protein.
Marta J Gonzalez-Hernandez, James D Cavalcoli, Maureen A Sartor, Rafael Contreras-Galindo, Fan Meng, Manhong Dai, Derek Dube, Anjan K Saha, Scott D Gitlin, Gilbert S Omenn, Mark H Kaplan, David M Markovitz
Author Information
Marta J Gonzalez-Hernandez: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA.
James D Cavalcoli: Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Maureen A Sartor: Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
Rafael Contreras-Galindo: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Fan Meng: Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA.
Manhong Dai: Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA.
Derek Dube: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Anjan K Saha: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Scott D Gitlin: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Department of Veterans Affairs, University of Michigan, Ann Arbor, Michigan, USA.
Gilbert S Omenn: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA School of Public Health, University of Michigan, Ann Arbor, Michigan, USA National Center for Integrative Biomedical Informatics, University of Michigan, Ann Arbor, Michigan, USA Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Mark H Kaplan: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
David M Markovitz: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA Program in Cancer Biology, University of Michigan, Ann Arbor, Michigan, USA Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA dmarkov@umich.edu.
Approximately 8% of the human genome is made up of endogenous retroviral sequences. As the HIV-1 Tat protein activates the overall expression of the human endogenous retrovirus type K (HERV-K) (HML-2), we used next-generation sequencing to determine which of the 91 currently annotated HERV-K (HML-2) proviruses are regulated by Tat. Transcriptome sequencing of total RNA isolated from Tat- and vehicle-treated peripheral blood lymphocytes from a healthy donor showed that Tat significantly activates expression of 26 unique HERV-K (HML-2) proviruses, silences 12, and does not significantly alter the expression of the remaining proviruses. Quantitative reverse transcription-PCR validation of the sequencing data was performed on Tat-treated PBLs of seven donors using provirus-specific primers and corroborated the results with a substantial degree of quantitative similarity. IMPORTANCE: The expression of HERV-K (HML-2) is tightly regulated but becomes markedly increased following infection with HIV-1, in part due to the HIV-1 Tat protein. The findings reported here demonstrate the complexity of the genome-wide regulation of HERV-K (HML-2) expression by Tat. This work also demonstrates that although HERV-K (HML-2) proviruses in the human genome are highly similar in terms of DNA sequence, modulation of the expression of specific proviruses in a given biological situation can be ascertained using next-generation sequencing and bioinformatics analysis.
