D4 Expression of Human Endogenous Retrovirus Type-K (HML-2) is Activated by the Tat Protein of HIV-1

Abstract

Human Endogenous Retroviruses (HERVs) make up 8% of the human genome. Expression of HERV-K (HML-2), our most recent genome entrant, is tightly regulated but becomes markedly increased following infection with HIV-1. To better understand the mechanisms involved in this activation, we explored the role of the HIV-1 proteins in inducing expression of these retroviral genes. Transfection experiments showed that, out of all HIV-1 proteins, Tat and Vif where the only ones inducing significant activation of HERV-K (HML-2) gene expression. Out of these two proteins, Tat alone was sufficient to cause significant HERV-K (HML-2) expression. Administration of recombinant HIV-1 Tat protein caused a 13-fold increase in HERV-K (HML-2) gag transcripts in Jurkat T cells and a 10-fold increase in primary lymphocytes, and expression of the HERV-K (HML-2) rec and np9 oncogenes was also markedly increased. Additionally, transfection of a plasmid encoding Tat caused a strong increase in HERV-K (HML-2) gag protein expression. Luciferase reporter gene assays demonstrated that the effect of Tat on HERV-K (HML-2) expression occurred at the level of the transcriptional promoter. The transcription factors NF-kB and NF-AT contribute to the Tat-induced activation of the promoter, as shown by mutational analysis of the HERV-K (HML-2) LTR, ChIP assays, and treatments with agents that inhibit NF-AT or NF-kB activation. These studies show that HIV-1 Tat plays an important role in activating expression of HERV-K (HML-2) in the setting of HIV-1 infection. By increasing expression of HERV-K oncogenes, Tat might potentiate HIV-related disease, but increased expression of HERV-K antigens might also contribute to immunological control of HIV infection.