Inhibition of human endogenous retrovirus-K by antiretroviral drugs.
Human endogenous retroviruses (HERVs) are genomic sequences of retroviral origin which were believed to be integrated into germline chromosomes millions of years ago and account for nearly 8% of the human genome. Although mostly defective and inactive, some of the HERVs may be activated under certain physiological and pathological conditions. While no drugs are designed specifically targeting HERVs, there are a panel of antiretroviral drugs designed against the human immunodeficiency virus and approved by the Federal Drug Administration (FDA).



We determined if these antiretroviral drugs may also be effective in inhibiting HERVs. We constructed a plasmid with consensus HERV-K sequence for testing the effect of antiretroviral drugs on HERV-K. We first determined the effects of nucleoside and non-nucleotide reverse transcriptase (RT) inhibitors on HERV-K by product enhanced reverse transcription assay. We found that all RT inhibitors could significantly inhibit HERV-K RT activity. To determine the effects of antiretroviral drugs on HERV-K infection and viral production, we pseudotyped HERV-K with VSV-G and used the pseudotyped HERV-K virus to infect HeLa cells. HERV-K production was measured by quantitative real time polymerase chain reaction. We found that RT inhibitors Abacavir and Zidovudine, and integrase inhibitor Raltegravir could effectively block HERV-K infection and production. However, protease inhibitors were not as effective as RT and integrase inhibitors.



In summary, we identified several FDA approved antiretroviral drugs that can effectively inhibit HERV-K. These antiretrovirals may open new prospects for studying HERV-K pathophysiology and potentially for exploring treatment of diseases in which HERV-K has been implicated.
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-103, Bldg 10, 10 Center Drive, Bethesda, MD, 20892, USA.
Richa
R
Tyagi
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-103, Bldg 10, 10 Center Drive, Bethesda, MD, 20892, USA.
Wenxue
W
Li
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-103, Bldg 10, 10 Center Drive, Bethesda, MD, 20892, USA.
Danelvis
D
Parades
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.|Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, USA.
Mario A
MA
Bianchet
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-103, Bldg 10, 10 Center Drive, Bethesda, MD, 20892, USA. natha@ninds.nih.gov.
Avindra
A
Nath
D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D020077:Endogenous Retroviruses / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D060888:Real-Time Polymerase Chain Reaction; D011995:Recombination, Genetic; D018116:Vesiculovirus / Q000235:genetics / Q000254:growth & development
D044966:Anti-Retroviral Agents
Amyotrophic lateral sclerosis; Antiretroviral; Comparative modeling; HIV; Human endogenous retrovirus-K