Inhibition of human endogenous retrovirus-K by antiretroviral drugs

Richa Tyagi,Mario A Bianchet,Avindra Nath,Danelvis Parades,Wenxue Li

doi:10.1186/s12977-017-0347-4

Abstract

BackgroundHuman 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).ResultsWe 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.ConclusionsIn 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.

Highlights

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
Because HIV-1 Rev can significantly enhance the transcription of human ERV-K (HERV-K) viral gene, an HIV-1 Rev expression cassette was inserted into the construct which we have termed pCD-HK/Rev (Fig. 1a)
The HERV-K reverse transcriptase (RT) quantification using this standard curve is only relative to HIV RT, not an absolute RT activity

Summary

Introduction

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. Initial drugs targeted reverse transcriptase (RT), drugs are available that target all major parts of the viral life cycle This includes blockage at viral entry, integrase (IN) inhibitors that prevent integration of proviral DNA into the chromosomal DNA, protease inhibitors that prevent cleavage of the Gag–Pol polyprotein and maturation inhibitors. In some HERV-K sequences there is a deletion of 292 base pairs at the pol–env junction as a result Rec is not formed [8] This resulted in an mRNA for a ~9 kDa fusion protein referred to as Np9, the function of which is not yet understood. Since HERV-K has its own RT, protease and IN, we screened a panel of FDA approved anti-HIV drugs that target these enzymes, for their ability to inhibit HERV-K

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