Activation of LTRs from Different Human Endogenous Retrovirus (HERV) Families by the HTLV-1 Tax Protein and T-Cell Activators

Abstract

Human endogenous retroviruses (HERVs) represent approximately 8% of our genome. HERVs influence cellular gene expression and contribute to normal physiological processes such as cellular differentiation and morphogenesis. HERVs have also been associated with certain pathological conditions, including cancer and neurodegenerative diseases. As HTLV-1 causes adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has been shown to modulate host gene expression mainly through the expression of the powerful Tax transactivator, herein we were interested in looking at the potential modulation capacity of HTLV-1 Tax on HERV expression. In order to evaluate the promoter activity of different HERV LTRs, pHERV-LTR-luc constructs were co-transfected in Jurkat T-cells with a Tax expression vector. Tax expression potently increased the LTR activity of HERV-W8 and HERV-H (MC16). In parallel, Jurkat cells were also stimulated with different T-cell-activating agents and HERV LTRs were observed to respond to different combination of Forskolin, bpV[pic] a protein tyrosine phosphatase inhibitor, and PMA. Transfection of expression vectors for different Tax mutants in Jurkat cells showed that several transcription factors including CREB appeared to be important for HERV-W8 LTR activation. Deletion mutants were derived from the HERV-W8 LTR and the region from −137 to −123 was found to be important for LTR response following Tax expression in Jurkat cells, while a different region was shown to be required in cells treated with activators. Our results thus demonstrated that HTLV-1 Tax activates several HERV LTRs. This raises the possibility that upregulated HERV expression could be involved in diseases associated with HTLV-1 infection.

HIV-1 Infection Leads to Increased Transcription of Human Endogenous Retrovirus HERV-K (HML-2) ProvirusesIn Vivobut Not to Increased Virion Production

“…2A). While HTLV Tax was associated with HERV transcription in one study (50), HTLV infection was not associated with HML-2-specific immune responses, differing from HIV (51). Infection with various herpesviruses has been associated with an increase in HERV transcription (52)(53)(54), although its impact on eliciting virions in vivo is unknown.…”

Expression of Human Endogenous Retrovirus Type K (HML-2) Is Activated by the Tat Protein of HIV-1

“…However, in general, how or why HERV genes are expressed, and the mechanisms responsible for expression, is not clearly understood. It is known that exogenous viral infections, viral transactivators, processes such as inflammation, chemical agents, cytokines, hormones, and stress conditions can contribute to the activation and transcription of transposable genetic elements, HERV-K (HML-2) being an example (21,26,39,55,57,60,66,68,71,94,101,114,116,121,122,125,127). A possible role for HERV-K (HML-2) in pathogenesis has been considered in disorders such as systemic lupus erythematosus, rheumatoid arthritis, and neuroinflammation (3,36,43,53,77,90,112,113).…”

The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)

“…Relative levels of transcripts encoding HERV-W elements and cellular genes are transactivated by viral infection in different cell lines by regulating the transcriptional activity (68). Several HERV LTRs could be activated by HTLV Tax and were involved in diseases (65). High-level expression of HERV-K has been demonstrated to be activated by the MITF-M gene in melanomas, breast cancers and teratocarcinomas (69).…”

“…HERV LTR could also be reactivated by environmental factors including cytokines (62), radiation (63,64) and proteins of exogenous retroviruses (65,66). Radiation induced the epigenetic regulation of HERV-R 5'LTR and upregulated HERV-R env expression (63).…”