HIV-1 Transcriptional Activator Tat Inhibits IL2 Expression by Preventing the Presence of Pol II on the IL2 Promoter

Biomolecules. 2023 May 24;13(6):881. doi: 10.3390/biom13060881.

Abstract

HIV-1 infection leads to a gradual loss of T helper cells, chronic immune activation, and eventual immune system breakdown. HIV-1 causes deregulation of the expression of IL-2, a cytokine important for T helper cell growth and survival, which is downregulated in HIV-1 patients. The present study addresses the regulation of IL2 expression via HIV-1 Tat transcriptional activator. We used J-LAT cells, a T cell line that serves as a latency model for studies of HIV-1 expression in T cells, and as controls a T cell line lacking HIV-1 elements and a T cell line with a stably integrated copy of the HIV-1-LTR promoter. We show that endogenously expressed Tat inhibits IL2 transcription in J-Lat cells via its presence in the ARRE-1/2 elements of the IL2 promoter and that the inhibition of IL2 expression is mediated by Tat inhibiting Pol II activity at the IL2 promoter, which is mediated by preventing the presence of Pol II at the ARRE-1/2 elements. Overall, Tat is present at the IL2 promoter, apart from its cognate HIV-1 LTR target. This supports our current knowledge of how HIV-1 affects the host transcriptional machinery and reflects the potential of Tat to disrupt transcriptional regulation of host genes to manipulate cell responses.

Keywords: HIV-1; IL2; J-LAT; NFAT2; Pol II; Tat; transcription factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation, Viral
  • HIV Infections* / genetics
  • HIV Infections* / immunology
  • HIV Infections* / virology
  • HIV-1* / genetics
  • HIV-1* / metabolism
  • Humans
  • Interleukin-2* / genetics
  • Interleukin-2* / metabolism
  • RNA Polymerase II* / genetics
  • RNA Polymerase II* / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • tat Gene Products, Human Immunodeficiency Virus* / genetics
  • tat Gene Products, Human Immunodeficiency Virus* / metabolism

Substances

  • Interleukin-2
  • RNA Polymerase II
  • tat Gene Products, Human Immunodeficiency Virus
  • Transcription Factors

Grants and funding

This work was funded by grants from the Hellenic Institute of State Scholarships (IKY) (to S.A.) and GILEAD-ASKLEPIOS grants for 2018 and 2019 (to A.M.). The funders had no influence on the study design, data collection and analysis, decision to publish, or preparation of the manuscript.